Modulators of the gpr119 receptor and the treatment of disorders related thereto

ABSTRACT

The present invention relates to the GPR119 receptor agonists: 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzanide; -fluoro-4-(5-fluoro-6-(4-(3-(2-fluoro-propan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide; and 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful as a single pharmaceutical agent or in combination with one or more additional pharmaceutical agents, such as, a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

FIELD OF THE INVENTION

The present invention relates to the GPR119 receptor agonists:3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide;3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide;and3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzamide,and pharmaceutically acceptable salts, solvates, and hydrates thereof,that are useful as a single pharmaceutical agent or in combination withone or more additional pharmaceutical agents, such as, a DPP-IVinhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulinanalogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, athiazolidinedione, or an anti-diabetic peptide analogue, in thetreatment of, for example, a disorder selected from: aGPR119-receptor-related disorder; a condition ameliorated by increasingsecretion of an incretin; a condition ameliorated by increasing a bloodincretin level; a condition characterized by low bone mass; aneurological disorder; a metabolic-related disorder; type 2 diabetes;obesity; and complications related thereto.

BACKGROUND OF THE INVENTION

A. Diabetes Mellitus

Diabetes mellitus is a serious disease afflicting over 100 millionpeople worldwide. In the United States, there are more than 12 milliondiabetics, with 600,000 new cases diagnosed each year.

Diabetes mellitus is a diagnostic term for a group of disorderscharacterized by abnormal glucose homeostasis resulting in elevatedblood sugar. There are many types of diabetes, but the two most commonare type 1 (also referred to as insulin-dependent diabetes mellitus orIDDM) and type 2 (also referred to as non-insulin-dependent diabetesmellitus or NIDDM).

The etiology of the different types of diabetes is not the same;however, everyone with diabetes has two things in common: overproductionof glucose by the liver and little or no ability to move glucose out ofthe blood into the cells where it becomes the body's primary fuel.

People who do not have diabetes rely on insulin, a hormone made in thepancreas, to move glucose from the blood into the cells of the body.However, people who have diabetes either do not produce insulin or cannot efficiently use the insulin they produce; therefore, they can notmove glucose into their cells. Glucose accumulates in the blood creatinga condition called hyperglycemia, and over time, can cause serioushealth problems.

Diabetes is a syndrome with interrelated metabolic, vascular, andneuropathic components. The metabolic syndrome, generally characterizedby hyperglycemia, comprises alterations in carbohydrate, fat and proteinmetabolism caused by absent or markedly reduced insulin secretion and/orineffective insulin action. The vascular syndrome consists ofabnormalities in the blood vessels leading to cardiovascular, retinaland renal complications. Abnormalities in the peripheral and autonomicnervous systems are also part of the diabetic syndrome.

About 5% to 10% of the people who have diabetes have IDDM. Theseindividuals do not produce insulin and therefore must inject insulin tokeep their blood glucose levels normal. IDDM is characterized by low orundetectable levels of endogenous insulin production caused bydestruction of the insulin-producing beta cells of the pancreas, thecharacteristic that most readily distinguishes IDDM from NIDDM. IDDM,once termed juvenile-onset diabetes, strikes young and older adultsalike.

Approximately 90% to 95% of people with diabetes have NIDDM (type 2).NIDDM subjects produce insulin, but the cells in their bodies areinsulin resistant: the cells do not respond properly to the hormone, soglucose accumulates in their blood. NIDDM is characterized by a relativedisparity between endogenous insulin production and insulinrequirements, leading to elevated blood glucose levels. In contrast toIDDM, there is always some endogenous insulin production in NIDDM; manyNIDDM patients have normal or even elevated blood insulin levels, whileother NIDDM patients have inadequate insulin production (Rotwein, R. etal. N. Engl. J. Med. 308, 65-71 (1983)). Most people diagnosed withNIDDM are age 30 or older, and half of all new cases are age 55 andolder. Compared with whites and Asians, NIDDM is more common amongNative Americans, African-Americans, Latinos, and Hispanics. Inaddition, the onset can be insidious or even clinically inapparent,making diagnosis difficult.

The primary pathogenic lesion on NIDDM has remained elusive. Many havesuggested that primary insulin resistance of the peripheral tissues isthe initial event. Genetic epidemiological studies have supported thisview. Similarly, insulin secretion abnormalities have been argued as theprimary defect in NIDDM. It is likely that both phenomena are importantcontributors to the disease process (Rimoin, D. L., et. al. Emery andRimoin's Principles and Practice of Medical Genetics 3^(rd) Ed.1:1401-1402 (1996)).

Many people with NIDDM have sedentary lifestyles and are obese: theyweigh approximately 20% more than the recommended weight for theirheight and build. Furthermore, obesity is characterized byhyperinsulinemia and insulin resistance, a feature shared with NIDDM,hypertension and atherosclerosis.

The patient with diabetes faces a 30% reduced lifespan. After age 45,people with diabetes are about three times more likely than peoplewithout diabetes to have significant heart disease and up to five timesmore likely to have a stroke. These findings emphasize theinter-relations between risks factors for NIDDM and coronary heartdisease and the potential value of an integrated approach to theprevention of these conditions (Perry, I. J., et al., BMJ 310, 560-564(1995)).

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous-system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina at theback of the eye and increases risk of cataracts and glaucoma. Finally,diabetes is associated with nerve damage, especially in the legs andfeet, which interferes with the ability to sense pain and contributes toserious infections. Taken together, diabetes complications are one ofthe nation's leading causes of death.

B. Obesity

Obesity and diabetes are among the most common human health problems inindustrialized societies. In industrialized countries a third of thepopulation is at least 20% overweight. In the United States, thepercentage of obese people has increased from 25% at the end of the1970's, to 33% at the beginning the 1990's. Obesity is one of the mostimportant risk factors for NIDDM. Definitions of obesity differ, but ingeneral, a subject weighing at least 20% more than the recommendedweight for his/her height and build is considered obese. The risk ofdeveloping NIDDM is tripled in subjects 30% overweight, andthree-quarters with NIDDM are overweight.

Obesity, which is the result of an imbalance between caloric intake andenergy expenditure, is highly correlated with insulin resistance anddiabetes in experimental animals and human. However, the molecularmechanisms that are involved in obesity-diabetes syndromes are notclear. During early development of obesity, increased insulin secretionbalances insulin resistance and protects patients from hyperglycemia (LeStunff, et al. Diabetes 43, 696-702 (1989)). However, after severaldecades, β cell function deteriorates and non-insulin-dependent diabetesdevelops in about 20% of the obese population (Pederson, P. Diab. Metab.Rev. 5, 505-509 (1989)) and (Brancati, F. L., et al., Arch. Intern. Med.159, 957-963 (1999)). Given its high prevalence in modern societies,obesity has thus become the leading risk factor for NIDDM (Hill, J. O.,et al., Science 280, 1371-1374 (1998)). However, the factors whichpredispose a fraction of patients to alteration of insulin secretion inresponse to fat accumulation remain unknown.

Whether someone is classified as overweight or obese can be determinedby a number of different methods, such as, on the basis of their bodymass index (BMI) which is calculated by dividing body weight (kg) byheight squared (m²). Thus, the units of BMI are kg/m² and it is possibleto calculate the BMI range associated with minimum mortality in eachdecade of life. Overweight is defined as a BMI in the range 25-30 kg/m²,and obesity as a BMI greater than 30 kg/m² (see table below). There areproblems with this definition, such as, it does not take into accountthe proportion of body mass that is muscle in relation to fat (adiposetissue). To account for this, alternatively, obesity can be defined onthe basis of body fat content: greater than 25% and 30% in males andfemales, respectively.

Classification of Weight by Body Mass Index (BMI)

BMI CLASSIFICATION <18.5 Underweight 18.5-24.9 Normal 25.0-29.9Overweight 30.0-34.9 Obesity (Class I) 35.0-39.9 Obesity (Class II) >40Extreme Obesity (Class III)

As the BMI increases there is an increased risk of death from a varietyof causes that is independent of other risk factors. The most commondiseases associated with obesity are cardiovascular disease(particularly hypertension), diabetes (obesity aggravates thedevelopment of diabetes), gall bladder disease (particularly cancer) anddiseases of reproduction. Research has shown that even a modestreduction in body weight can correspond to a significant reduction inthe risk of developing coronary heart disease.

Obesity considerably increases the risk of developing cardiovasculardiseases as well. Coronary insufficiency, atheromatous disease, andcardiac insufficiency are at the forefront of the cardiovascularcomplication induced by obesity. It is estimated that if the entirepopulation had an ideal weight, the risk of coronary insufficiency woulddecrease by 25% and the risk of cardiac insufficiency and of cerebralvascular accidents by 35%. The incidence of coronary diseases is doubledin subjects less than 50 years of age who are 30% overweight.

C. Atherosclerosis

Atherosclerosis is a complex disease characterized by inflammation,lipid accumulation, cell death and fibrosis. Atherosclerosis ischaracterized by cholesterol deposition and monocyte infiltration intothe subendothelial space, resulting in foam cell formation. Thrombosissubsequent to atherosclerosis leads to myocardial infarction and stroke.Atherosclerosis is the leading cause of mortality in many countries,including the United States. (See, e.g., Ruggeri, Nat Med (2002)8:1227-1234; Arehart et al., Circ Res, Circ. Res. (2008) 102:986-993.)

D. Osteoporosis

Osteoporosis is a disabling disease characterized by the loss of bonemass and microarchitectural deterioration of skeletal structure leadingto compromised bone strength, which predisposes a patient to increasedrisk of fragility fractures. Osteoporosis affects more than 75 millionpeople in Europe, Japan and the United States, and causes more than 2.3million fractures in Europe and the United States alone. In the UnitedStates, osteoporosis affects at least 25% of all post-menopausal whitewomen, and the proportion rises to 70% in women older than 80 years. Onein three women older than 50 years will have an osteoporotic fracturethat causes a considerable social and financial burden on society. Thedisease is not limited to women; older men also can be affected. By2050, the worldwide incidence of hip fracture projected to increase by310% in men and 240% in women. The combined lifetime risk for hip,forearm, and vertebral fractures presenting clinically is around 40%,equivalent to the risk for cardiovascular disease. Osteoporoticfractures therefore cause substantial mortality, morbidity, and economiccost. With an ageing population, the number of osteoporotic fracturesand their costs will at least double in the next 50 years unlesseffective preventive strategies are developed. (See, e.g., Atik et al.,Clin. Orthop. Relat. Res. (2006) 443:19-24; Raisz, J. Clin. Invest.(2005) 115:3318-3325; and World health Organization Technical ReportSeries 921 (2003), Prevention and Management of Osteoporosis).

E. Inflammatory Bowel Disease (IBD)

Inflammatory bowel disease (IBD) is the general name for diseases thatcause inflammation in the intestines and includes, e.g. Crohn's disease,ulcerative colitis, and ulcerative proctitis. U.S. medical costs ofinflammatory bowel disease for 1990 have been estimated to be $1.4 to$1.8 billion. Lost productivity has been estimated to have added anadditional $0.4 to $0.8 billion, making the estimated cost ofinflammatory bowel disease $1.8 to $2.6 billion. (See, e.g., Pearson,Nursing Times (2004) 100:86-90; Hay el al., J. Clin. Gastroenterol.(1992) 14:309-317; Keighley et al., Ailment Pharmacol. Ther. (2003)18:66-70).

Enteritis refers to inflammation of the intestine, especially the smallintestine, a general condition that can have any of numerous differentcauses. Enterocolitis refers to inflammation of the small intestine andcolon.

Crohn's disease (CD) is an inflammatory process that can affect anyportion of the digestive tract, but is most commonly seen in the lastpart of the small intestine otherwise called the (terminal) ileum andcecum. Altogether this area is also known as the ileocecal region. Othercases may affect one or more of: the colon only, the small bowel only(duodenum, jejunum and/or ileum), the anus, stomach or esophagus. Incontrast with ulcerative colitis, CD usually does not affect the rectum,but frequently affects the anus instead. The inflammation extends deepinto the lining of the affected organ. The inflammation can cause painand can make the intestines empty frequently, resulting in diarrhea. CDmay also be called enteritis. Granulomatous colitis is another name forCD that affects the colon. Ileitis is CD of the ileum which is the thirdpart of the small intestine. Crohn's colitis is CD affecting all or partof the colon.

Ulcerative colitis (UC) is an inflammatory disease of the largeintestine, commonly called the colon. UC causes inflammation andulceration of the inner lining of the colon and rectum. The inflammationof UC is usually most severe in the rectal area with severitydiminishing (at a rate that varies from patient to patient) toward thececum, where the large and small intestines join together. Inflanunationof the rectum is called proctitis. Inflammation of the sigmoid colon(located just above the rectum) is called sigmoiditis. Inflammationinvolving the entire colon is termed pancolitis. The inflammation causesthe colon to empty frequently resulting in diarrhea. As the lining ofthe colon is destroyed ulcers form releasing mucus, pus and blood.Ulcerative proctitis is a form of UC that affects only the rectum.

F. GPR119

GPR119 is a G protein-coupled receptor (GPR119; e.g., human GPR119,GenBank® Accession No. AAP72125 and alleles thereof; e.g., mouse GPR119,GenBank® Accession No. AY288423 and alleles thereof) and is selectivelyexpressed on pancreatic beta cells. GPR119 activation leads to elevationof a level of intracellular cAMP, consistent with CPR119 being coupledto Gs. Agonists to GPR119 stimulate glucose-dependent insulin secretionin vitro and lower an elevated blood glucose level in vivo; see, e.g.,International Applications WO 04/065380 and WO 04/076413, and EP1338651. In the literature, GPR119 has also been referred to as RUP3(see, International Application WO 00/31258) and as Glucose-DependentInsulinotropic Receptor GDIR (see, Jones, et. al. Expert Opin. Ther.Patents (2009), 19(10): 1339-1359).

GPR119 agonists also stimulate the release of Glucose-dependentInsulinotropic Polypeptide (GIP), Glucagon-Like Peptide-1 (GLP-1), andat least one other L-cell peptide, Peptide YY (PYY) (Jones, et. al.Expert Opin. Ther. Patents (2009), 19(10): 1339-1359); for specificreferences related to GPR119 agonists and the release of:

GIP, see Shah, Current Opinion in Drug Discovery & Development, (2009)12:519-532; Jones, et al., Ann. Rep. Med. Chem., (2009) 44:149-170; WO2007/120689; and WO 2007/120702;

GLP-1, see Shah, Current Opinion in Drug Discovery & Development, (2009)12:519-532; Jones, et al., Ann. Rep. Med. Chem., (2009) 44:149-170;Schwartz et. al., Cell Metabolism, 2010, 11:445-447; and WO 2006/076231;and

PYY, see Schwartz et. al., Cell Metabolism, 2010, 11:445-447; and WO2009/126245.

As mentioned above, GPR119 agonists enhance incretin release andtherefore can be used in treatment of disorders related to theincretins, such as, GIP, GLP-1, and PYY. However, a number of theincretins, such as, GIP and GLP-1, are substrates for the enzymedipeptidyl peptidase-4 (DPP-IV). Jones and co-workers (Jones, et al.,Ann. Rep. Med. Chem., (2009) 44:149-170) have demonstrated that acombined administration of a GPR119 agonist,(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine(see, Compound B111 in WO 2004/065380), and a DPP-IV inhibitor acutelyincreased plasma GLP-1 levels and improved glucose tolerance to asignificantly greater degree than either agent alone.

G. Glucose-Dependent Insulinotropic Polypeptide (GIP)

Glucose-dependent insulinotropic polypeptide (GIP, also known as gastricinhibitory polypeptide) is a peptide incretin hormone of 42 amino acidsthat is released from duodenal endocrine K cells after meal ingestion.The amount of GIP released is largely dependent on the amount of glucoseconsumed. GIP has been shown to stimulate glucose-dependent insulinsecretion in pancreatic beta cells. GIP mediates its actions through aspecific G protein-coupled receptor, namely GIPR.

As GIP contains an alanine at position 2, it is an excellent substratefor DPP-IV, an enzyme regulating the degradation of GIP. Full-lengthGIP(1-42) is rapidly converted to bioinactive GIP(3-42) within minutesof secretion from the endocrine K cell. Inhibition of DPP-IV has beenshown to augment GIP bioactivity. (See, e.g., Drucker, Cell Metab (2006)3:153-165; McIntosh et al., Regul Pept (2005) 128:159-165; Deacon, RegulPept (2005) 128:117-124; and Ahren et al., Endocrinology (2005)146:2055-2059.). Analysis of full length bioactive GIP, for example inblood, can be carried out using N-terminal-specific assays (see, e.g.,Deacon et al., J Clin Endocrinol Metab (2000) 85:3575-3581).

Recently, GIP has been shown to promote bone formation. GIP has beenshown to activate osteoblastic receptors, resulting in increases incollagen type I synthesis and alkaline phosphatase activity, bothassociated with bone formation. GIP has been shown to inhibit osteoclastactivity and differentiation in vitro. GIP administration has been shownto prevent the bone loss due to ovariectomy. GIP receptor (GIPR)knockout mice evidence a decreased bone size, lower bone mass, alteredbone microarchitecture and biochemical properties, and alteredparameters for bone turnover, especially in bone formation. (See, e.g.,Zhong et al., Am J Physiol Endocrinol Metab (2007) 292:E543-E548; Bollaget al., Endocrinology (2000) 141:1228-1235; Bollag et al., Mol CellEndocrinol (2001) 177:35-41; Xie et al., Bone (2005) 37:759-769; andTsukiyama et al., Mol Endocrinol (2006) 20:1644-1651.)

The usefulness of GIP for maintaining or increasing bone density orformation has been acknowledged by the United States Patent andTrademark Office by issuance of U.S. Pat. No. 6,410,508 for thetreatment of reduced bone mineralization by administration of GIPpeptide. However, current GIP peptide agonists suffer from a lack oforal bioavailability, negatively impacting patient compliance. Anattractive alternative approach is to develop an orally activecomposition for increasing an endogenous level of GIP activity.

GPR119 agonists have been shown to stimulate the release of GIP; seeShah, Current Opinion in Drug Discovery & Development, (2009)12:519-532; Jones, et al., Ann. Rep. Med. Chem., (2009) 44:149-170; WO2007/120689; and WO 2007/120702.

H. Glucagon-Like Peptide-1 (GLP-1)

Glucagon-like peptide-1 (GLP-1) is an incretin hormone derived from theposttranslational modification of proglucagon and secreted by gutendocrine cells. GLP-1 mediates its actions through a specific Gprotein-coupled receptor (GPCR), namely GLP-1R. GLP-1 is bestcharacterized as a hormone that regulates glucose homeostasis. GLP-1 hasbeen shown to stimulate glucose-dependent insulin secretion and toincrease pancreatic beta cell mass. GLP-1 has also been shown to reducethe rate of gastric emptying and to promote satiety. The efficacy ofGLP-1 peptide agonists in controlling blood glucose in type 2 diabeticshas been demonstrated in several clinical studies [see, e.g., Nauck etal., Drug News Perspect (2003) 16:413-422], as has its efficacy inreducing body mass [Zander et al., Lancet (2002) 359:824-830].

GLP-1 receptor agonists are additionally useful in protecting againstmyocardial infarction and against cognitive and neurodegenerativedisorders. GLP-1 has been shown to be cardioprotective in a rat model ofmyocardial infarction [Bose et al., Diabetes (2005) 54:146-151], andGLP-1R has been shown in rodent models to be involved in learning andneuroprotection [During et al., Nat. Med. (2003) 9:1173-1179; and Greiget al., Ann N Y Acad Sci (2004) 1035:290-315].

Certain disorders such as type 2 diabetes are characterized by adeficiency in GLP-1 [see, e.g., Nauck et al., Diabetes (2004) 53 Suppl3:S190-196].

Current GLP-1 peptide agonists suffer from a lack of oralbioavailability, negatively impacting efficacy. Efforts to developorally bioavailable non-peptidergic, small-molecule agonists of GLP-1Rhave so far been unsuccessful (Mentlein, Expert Opin Investig Drugs(2005) 14:57-64). An attractive alternative approach is to develop anorally active composition for increasing an endogenous level of GLP-1 inthe blood.

GPR119 agonists have been shown to stimulate the release of GLP-1, seeShah, Current Opinion in Drug Discovery & Development, (2009)12:519-532; Jones, et al., Ann. Rep. Med. Chem., (2009) 44:149-170;Schwartz et. al., Cell Metabolism, 2010, 11:445-447; and WO 2006/076231.

I. Peptide YY (PYY)

Peptide YY (PYY) is a 36 amino acid peptide originally isolated in 1980from porcine intestine (Tatemoto et al., Nature (1980) 285:417-418). PYYis secreted from enteroendocrine L-cells within both the large and smallintestine. It has been shown that in rat and human gut concentrations ofimmunoreactive PYY are low in duodenum and jejunum, high in ileum andcolon, and highest in rectum (Lundberg et al., PNAS USA (1982)79:4471-4475; Adrian et al., Gastroenterol. (1985) 89:1070-1077; Ekbladet al., Peptides (2002) 23:251-261; Ueno et al., Regul Pept (2008)145:12-16). PYY expression in rat has also been reported to extend toalpha cells of the islets of Langerhans and to cells in the medullaoblongata (Ekblad et al., Peptides (2002) 23:251-261); PYY is releasedinto the circulation as PYY₁₋₃₆ and PYY₃₋₃₆ (Eberlein et al., Peptides(1989) 10:797-803). PYY₃₋₃₆ is generated from PYY₁₋₃₆ by cleavage of theN-terminal Tyr and Pro residues by DPP-IV. PYY₃₋₃₆ is the predominantform of PYY in human postprandial plasma (Grandt et al., Regul. Pept.(1994) 51:151-159). PYY₁₋₃₆ and PYY₃₋₃₆ have been reported to havecomparable agonist activity at NPY Y2 receptor (Y2R), a Gprotein-coupled receptor (Parker et al., Br. J. Pharmacol. (2008)153:420-431); however, PYY₃₋₃₆ has been reported to be a high-affinityY2R selective agonist (Keire et al., Am. J. Physiol. Gastrointest. LiverPhysiol. (2000) 279:G126-G131). PYY was subsequently reported to reducehigh-fat food intake in rats after peripheral administration (Okada etal., Endocrinology Supplement (1993) 180) and to cause weight loss inmice after peripheral administration (Morley et al., Life Sciences(1987) 41:2157-2165).

Peripheral administration of PYY₃₋₃₆ has been reported to markedlyreduce food intake and weight gain in rats, to decrease appetite andfood intake in humans, and to decrease food intake in mice, but not inY2R-null mice, which was said to suggest that the food intake effectrequires the Y2R. In human studies, infusion of PYY₃₋₃₆ was found tosignificantly decrease appetite and reduce food intake by 33% over 24hours. Infusion of PYY₃₋₃₆ to reach the normal postprandial circulatoryconcentrations of the peptide led to peak serum levels of PYY₃₋₃₆ within15 minutes, followed by a rapid decline to basal levels within 30minutes. It was reported that there was significant inhibition of foodintake in the 12-hour period following the PYY₃₋₃₆ infusion, but thatthere was essentially no effect on food intake in the 12-hour to 24-hourperiod. In a rat study, repeated administration of PYY₃₋₃₆intraperitoneally (injections twice daily for 7 days) reduced cumulativefood intake (Batterham et al., Nature (2002) 418:650-654; Renshaw etal., Current Drug Targets (2005) 6:171-179).

Peripheral administration of PYY₃₋₃₆ has been reported to reduce foodintake, body weight gain and glycemic indices in diverse rodent modelsof metabolic diseases of both sexes (Pittner et al., Int. J. Obes.Relat. Metab. Disord. (2004) 28:963-971). It has been reported thatblockade of Y2R with the specific antagonist BIIE-246 attenuates theeffect of peripherally administered endogenous and exogenous PYY₃₋₃₆ forreducing food intake (Abbott et al., Brain Res (2005) 1043:139-144). Ithas been reported that peripheral administration of a novel long-actingselective Y2R polyethylene glycol-conjugated peptide agonist reducesfood intake and improves glucose metabolism (glucose disposal, plasmainsulin and plasma glucose) in rodents (Ortiz et al., JPET (2007)323:692-700; Lamb et al., J. Med. Chem. (2007) 50:2264-2268). It hasbeen reported that PYY ablation in mice leads to the development ofhyperinsulinemia and obesity (Boey et al., Diabetologia (2006)49:1360-1370). It has been reported that peripheral administration of along-acting, potent and highly selective Y2R agonist inhibits foodintake and promotes fat metabolism in mice (Balasubramaniam et al.,Peptides (2007) 28:235-240).

There is evidence that agents which stimulate PYY synthesis in vivo canconfer protection against diet-induced and genetic obesity and canimprove glucose tolerance (Boey et al., Neuropeptides (2008) 42:19-30).

It has been reported that Y2R agonists such as PYY₁₋₃₆ and PYY₃₋₃₆ canconfer protection against epileptic seizures, such as against kainatcseizures (El Bahh et al., Eur. J. Neurosci. (2005) 22:1417-1430; Woldbyeet al., Neurobiology of Disease (2005) 20:760-772).

It has been reported that Y2R agonists such as PYY₁₋₃₆ and PYY₃₋₃₆ actas proabsorbtive (or anti-secretory) hormones, increasing uponintravenous administration the absorption of both water and sodium invarious parts of the bowel (Bilchik et al., Gastroenterol. (1993)105:1441-1448; Liu et al., J. Surg. Res. (1995) 58:6-11; Nightingale etal., Gut (1996) 39:267-272; Liu et al., Am Surg (1996) 62:232-236;Balasubramaniam et al., J. Med. Chem. (2000) 43:3420-3427). It has beenreported that Y2R agonists such as PYY analogues inhibit secretion andpromote absorption and growth in the intestinal epithelium(Balasubramaniam et al., J. Med. Chem. (2000) 43:3420-3427). It has beenreported that PYY promotes intestinal growth in normal rats (Gomez etal., Am. J. Physiol. (1995) 268:G71-G81). It has been reported that Y2Ragonists such as PYY₁₋₃₆ and PYY₃₋₃₆ inhibit bowel motility and work toprevent diarrhea (EP1902730; also see Cox, Peptides (2007) 28:345-351).

It has been reported that Y2R agonists such as PYY₁₋₃₆ and PYY₃₋₃₆ canconfer protection against inflammatory bowel disease such as ulcerativecolitis and Crohn's disease (WO 03/105763). It has been reported thatPYY-deficient mice exhibit an osteopenic phenotype, i.e. that PYY canincrease bone mass and/or can confer protection against loss of bonemass (e.g., decreases loss of bone mass) (Wortley et al., Gastroenterol.(2007) 133:1534-1543). It has been reported that PYY₃₋₃₆ can conferprotection in rodent models of pancreatitis (Vona-Davis et al., Peptides(2007) 28:334-338).

It has been reported that angiogenesis is impaired in Y2R-deficient mice(Lee et al., Peptides (2003) 24:99-106), i.e. that agonists of Y2R suchas PYY₁₋₃₆ and PYY₃₋₃₆ promote angiogenesis. It has been reported thatwound healing is impaired in Y2R-deficient mice (Ekstrand et al., PNASUSA (2003) 100:6033-6038), i.e. that agonists of Y2R such as PYY₁₋₃₆ andPYY₃₋₃₆ promote wound healing. It has been reported that ischemicangiogenesis is impaired in Y2R-deficient mice (Lee et al., J. Clin.Invest. (2003) 111:1853-1862), i.e. that agonists of Y2R such as PYY₁₋₃₆and PYY₃₋₃₆ promotes revascularization and restoration of function ofischemic tissue. It has been reported that agonists of Y2R such asPYY₁₋₃₆ and PYY₃₋₃₆ mediate increases in collateral-dependent blood flowin a rat model of peripheral arterial disease (Cruze et al., Peptides(2007) 28:269-280).

It has been reported that PYY and Y2R agonists such as PYY₃₋₃₆ cansuppress tumor growth in the cases of, e.g., pancreatic cancer such aspancreatic ductal adenocarcinoma, breast cancer such as breastinfiltrative ductal adenocarcinoma, colon cancer such as colonadenocarcinoma and Barrett's adenocarcinoma (Liu el al, Surgery (1995)118:229-236; Liu el al., J. Surg. Res. (1995) 58:707-712; Grise et al.,J. Surg. Res. (1999) 82:151-155; Tseng et al., Peptides (2002)23:389-395; McFadden et al., Am. J. Surg. (2004) 188:516-519).

It has been reported that stimulation of Y2R such as by PYY₃₋₃₆ leads toan increase in plasma adiponectin (Ortiz et al., JPET (2007)323:692-700). Adiponectin is an adipokine with potent anti-inflammatoryproperties (Ouchi et al., Clin Chim Acta (2007) 380:24-30; Tilg et al.,Nat. Rev. Immunol (2006) 6:772-783). Adiponectin exerts anti-atherogeniceffects by targeting vascular endothelial cells and macrophages andinsulin-sensitizing effects, predominantly in muscle and liver (Kubotaet al., J. Biol. Chem. (2002) 277:25863-25866; Maeda et al., Nat. Med.(2002) 8:731-737). Low adiponectin levels have been reported to beassociated with atherogenic lipoproteins in dyslipidemia (elevatedtriglycerides, small dense LDL cholesterol, and low HDL cholesterol)(Marso et al., Diabetes Care (2008) 31:989-994). Adiponectin has beenimplicated in high density lipoprotein (IIDL) assembly (Oku et al., FEBSLetters (2007) 581:5029-5033). Adiponectin has been found to amelioratethe abnormalities of metabolic syndrome, including insulin resistance,hyperglycemia, and dyslipidemia, in a mouse model of obesity-linkedmetabolic syndrome associated with decreased adiponectin levels (Hara etal., Diabetes Care (2006) 29:1357-1362). Adiponectin has been reportedto stimulate angiogenesis in response to tissue ischemia (Shibata etal., J. Biol. Chem. (2004) 279:28670-28674). Adiponectin has beenreported to prevent cerebral ischemic injury through endothelial nitricoxide synthase-dependent mechanisms (Nishimura et al., Circulation(2008) 117:216-223). Adiponectin has been reported to confer protectionagainst myocardial ischemia-reperfusion injury (Shibata et al., Nat Med(2005) 11:1096-1103; Tao et al., Circulation (2007) 115:1408-1416).Adiponectin has been reported to confer protection against myocardialischemia-reperfusion injury via AMP-activated protein kinase, Akt, andnitric oxide (Gonon et al., Cardiovasc Res. (2008) 78:116-122).Adiponectin has been reported to confer protection against thedevelopment of systolic dysfunction following myocardial infarction,through its abilities to suppress cardiac hypertrophy and interstitialfibrosis, and protect against myocyte and capillary loss (Shibata etal., J. Mol. Cell Cardiol. (2007) 42:1065-1074). Adiponectin has beenreported to confer protection against inflammatory lung disease;adiponectin-deficient mice exhibit an emphysema-like phenotype (Summeret al., Am J. Physiol. Lung Cell Mol. Physiol (Mar. 7, 2008)).Adiponectin has been reported to confer protection against allergicairway inflammation and airway hyperresponsiveness such as may beassociated with asthma (Shore et al., J. Allergy Clin. Immunol (2006)118:389-395). Adiponectin has been suggested to confer protectionagainst pulmonary arterial hypertension by virtue of itsinsulin-sensitizing effects (Hansmann et al., Circulation (2007)115:1275-1284). Adiponectin has been reported to ameliorateobesity-related hypertension, with said amelioration of hypertensionbeing associated in part with upregulated prostacyclin expression(Ohashi et al, Hypertension (2006) 47:1108-1116). Adiponectin has beenreported to decrease tumor necrosis factor (TNF)-α-induced expression ofthe adhesion molecules VCAM-1, E-selectin and ICAM-1 in human aorticendothelial cells (HAECs) (Ouchi et al., Circulation (1999)100:2473-2476) and to inhibit production of TNF-α in macrophages (Yokotaet al., Blood (2000) 96:1723-1732). Adiponectin has been reported toconfer protection against restenosis after vascular intervention(Matsuda et al., J Biol Chem (2002) 277:37487-37491). The central roleof TNF-α in inflammation has been demonstrated by the ability of agentsthat block the action of TNF-α to treat a range of inflammatoryconditions. TNF-α-mediated inflammatory conditions encompass rheumatoidarthritis, inflammatory bowel disease such as Crohn's disease,ankylosing spondylitis, psoriasis, ischemic brain injury, cardiacallograft rejection, asthma, and the like (Bradley, J Pathol (2008)214:149-160). See, e.g., Yamamoto et al., Clinical Science (2002)103:137-142; Behre, Scand J Clin Lab Invest (2007) 67:449-458;Guerre-Millo, Diabetes & Metabolism (2008) 34:12-18; Parker et al., Br.J. Pharmacol. (2008) 153:420-431.

GPR119 agonists have been shown to stimulate the release of PYY; seeSchwartz et. al., Cell Metabolism, 2010, 11:445-447; and WO 2009/126245.

SUMMARY OF THE INVENTION

The present invention is drawn to3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Formula (Ia), Compound 1) and pharmaceutically acceptable salts,solvates, and hydrates thereof,

3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide(Formula (Ib), Compound 2) and pharmaceutically acceptable salts,solvates, and hydrates thereof,

and3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzamide(Formula(Ic), Compound 3) and pharmaceutically acceptable salts, solvates, andhydrates thereof,

which bind to and modulate the activity of a GPCR, referred to herein asGPR119, and uses thereof.

One aspect of the present invention pertains to compounds selected from3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Formula (Ia), Compound 1) and pharmaceutically acceptable salts,solvates, and hydrates thereof.

One aspect of the present invention pertains to compositions comprisinga compound of the present invention.

One aspect of the present invention pertains to compositions comprisinga compound of the present invention and a pharmaceutically acceptablecarrier.

One aspect of the present invention pertains to methods for preparing acomposition comprising the step of admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to pharmaceutical productsselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention.

One aspect of the present invention pertains to compositions comprisinga compound of the present invention and a second pharmaceutical agent.

One aspect of the present invention pertains to methods for preparing acomposition comprising the step of admixing a compound of the presentinvention and a second pharmaceutical agent.

One aspect of the present invention pertains to compositions comprisinga compound of the present invention, a second pharmaceutical agent, anda pharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for preparing acomposition comprising the step of admixing a compound of the presentinvention, a second pharmaceutical agent, and a pharmaceuticallyacceptable carrier.

One aspect of the present invention pertains to compositions obtained bya method of the present invention.

One aspect of the present invention pertains to a pharmaceuticalproducts selected from: a pharmaceutical composition, a formulation, adosage form, a combined preparation, a twin pack, and a kit; comprisinga compound of the present invention and a second pharmaceutical agent.

One aspect of the present invention pertains to methods for modulatingthe activity of a GPR119 receptor, comprising administering to anindividual in need thereof: a therapeutically effective amount of acompound of the present invention; a composition of the presentinvention; or a pharmaceutical product of the present invention.

One aspect of the present invention pertains to methods for modulatingthe activity of a GPR119 receptor, comprising prescribing to anindividual in need thereof: a therapeutically effective amount of acompound of the present invention; a composition of the presentinvention; or a pharmaceutical product of the present invention.

One aspect of the present invention pertains to the use of a compound ofthe present invention; or a composition of the present invention; in themanufacture of a medicament for modulating the activity of a GPR119receptor in an individual.

One aspect of the present invention pertains to a compound of thepresent invention; a composition of the present invention; or apharmaceutical product of the present invention; for use in a method oftreatment of the human or animal body by therapy.

One aspect of the present invention pertains to a compound of thepresent invention; a composition of the present invention; or apharmaceutical product of the present invention; for use in a method ofmodulating the activity of a GPR119 receptor in an individual.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention; for use in a method of treatment ofthe human or animal body by therapy.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention; for use in a method of modulating theactivity of a GPR119 receptor in an individual.

One aspect of the present invention pertains to compounds, methods,compositions, uses of compounds, and pharmaceutical products, each asdescribed herein, in combination with a second pharmaceutical agent. Forexample, one aspect of the present invention pertains to methods formodulating the activity of a GPR119 receptor, comprising administeringto an individual in need thereof, a therapeutically effective amount ofa compound of the present invention in combination with atherapeutically effective amount of a second pharmaceutical agent.

One aspect of the present invention pertains to compositions, methods,pharmaceutical products, uses, and compounds, each as described herein,in combination with a second pharmaceutical agent, wherein the secondpharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide,an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, anSGLT2 inhibitor, a meglitinide, a thiazolidinedione, and ananti-diabetic peptide analogue.

One aspect of the present invention pertains to compounds, methods,compositions, uses of compounds, and pharmaceutical products, each asdescribed herein, wherein modulating the activity of a GPR119 receptorin an individual is agonizing the GPR119 receptor.

One aspect of the present invention pertains to compounds, methods,compositions, uses of compounds, and pharmaceutical products, each asdescribed herein, wherein modulating the activity of a GPR119 receptorin an individual is increasing the secretion of an incretin.

One aspect of the present invention pertains to compounds, methods,compositions, uses of compounds, and pharmaceutical products, each asdescribed herein, wherein modulating the activity of a GPR119 receptorin an individual is increasing a blood incretin level.

One aspect of the present invention pertains to compounds, methods,compositions, uses of compounds, and pharmaceutical products, each asdescribed herein, wherein modulating the activity of a GPR119 receptorin an individual is treating a disorder, wherein the disorder isselected from: a GPR119-receptor-related disorder; a conditionameliorated by increasing secretion of an incretin; a conditionameliorated by increasing a blood incretin level; a conditioncharacterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity.

One aspect of the present invention pertains to compounds, methods,compositions, uses of compounds, and pharmaceutical products, each asdescribed herein, wherein the metabolic-related disorder is type 2diabetes.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effects of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamideon glucose homeostasis in male diabetic ZDF rats (oral glucose tolerancetest (oGTT)).

FIG. 2 shows the effects of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamideon percent glycemic inhibition in male diabetic ZDF rats.

FIG. 3 shows the effects of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamideon glucose homeostasis in male 129 SVE MICE (oGTT).

FIG. 4 shows the effects of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamideon percent glycemic inhibition in male 129 SVE mice.

FIG. 5 shows the in vivo effects of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamideon incretin hormone GIP release.

FIG. 6 shows the PXRD for the anhydrous form of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide.

FIG. 7 shows the DSC and TGA for the anhydrous form of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide.

FIG. 8 shows the DMS for the anhydrous form of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide.

FIG. 9 shows M1 metabolite formation in liver microsomal incubation(mouse, monkey, dog, rat, and human).

FIG. 10 shows M2 metabolite formation in liver microsomal incubation(mouse, monkey, dog, rat, and human).

FIG. 11 shows M3 metabolite formation in liver microsomal incubation(mouse, monkey, dog, rat, and human).

DETAILED DESCRIPTION OF THE INVENTION

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. Accordingly, all combinations of uses andmedical indications described herein specifically embraced by thepresent invention just as if each and every subcombination of uses andmedical indications was individually and explicitly recited herein.

Definitions

For clarity and consistency, the following definitions will be usedthroughout this patent document.

The term “agonist” as used herein refers to a moiety that interacts withand activates a G-protein-coupled receptor, for instance aGPR119-receptor, and can thereby initiate a physiological orpharmacological response characteristic of that receptor. For example,an agonist may activate an intracellular response upon binding to areceptor, or enhance GTP binding to a membrane. An agonist can be a fullagonist or a partial agonist.

The term “antagonist” as used herein refers to a moiety thatcompetitively binds to the receptor at the same site as an agonist (forexample, the endogenous ligand), but which does not activate theintracellular response initiated by the active form of the receptor andcan thereby inhibit the intracellular responses by an agonist or partialagonist. An antagonist does not diminish the baseline intracellularresponse in the absence of an agonist or partial agonist.

The term “GPR119” as used herein includes the human amino acid sequencesfound in GenBank accession number AY288416, and naturally-occurringallelic variants thereof, and mammalian orthologs thereof. A preferredhuman GPR119 for use in screening and testing of the compounds of theinvention is provided in the nucleotide sequence of Seq. ID. No:1 andthe corresponding amino acid sequence in Seq. ID. No:2 found in PCTApplication No. WO2005/007647.

The term “in need of treatment” and the term “in need thereof” whenreferring to treatment are used interchangeably and refer to a judgmentmade by a caregiver (e.g. physician, nurse, nurse practitioner, etc. inthe case of humans; veterinarian in the case of animals, includingnon-human mammals) that an individual or animal requires or will benefitfrom treatment. This judgment is made based on a variety of factors thatare in the realm of a caregiver's expertise, but that includes theknowledge that the individual, or will become ill, as the result of adisease, condition or disorder that is treatable by the compounds of theinvention. Accordingly, the compounds of the invention can be used in aprotective or preventive manner; or compounds of the invention can beused to alleviate, inhibit or ameliorate the disease, condition ordisorder.

The term “individual” refers to any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates, and most preferably humans.

The term “inverse agonist” refers to a moiety that binds to theendogenous form of the receptor or to the constitutively activated formof the receptor and which inhibits the baseline intracellular responseinitiated by the active form of the receptor below the normal base levelof activity which is observed in the absence of an agonist or partialagonist, or decreases GTP binding to a membrane. Preferably, thebaseline intracellular response is inhibited in the presence of theinverse agonist by at least 30%, more preferably by at least 50% andmost preferably by at least 75%, as compared with the baseline responsein the absence of the inverse agonist.

The term “modulate or modulating” refers to an increase or decrease inthe amount, quality, response or effect of a particular activity,function or molecule.

The term “composition” refers to a compound, including but not limitedto, a compound of the present invention and salts, solvates, andhydrates thereof, in combination with at least one additional component.

The term “pharmaceutical composition” refers to a composition comprisingat least one active ingredient, such as a compound of the presentinvention; including but not limited to, a compound of the presentinvention and salts, solvates, and hydrates thereof, whereby thecomposition is amenable for treating and/or investigating a specified,efficacious outcome in a mammal (for example, without limitation, ahuman). Those of ordinary skill in the art will understand andappreciate the techniques appropriate for determining whether an activeingredient has a desired efficacious outcome based upon the needs of theartisan.

The term “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician or caregiver or by an individual, which includes one or moreof the following:

(1) preventing the disease, for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) inhibiting the disease, for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and

(3) ameliorating the disease, for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

The term “weight management” as used herein means controlling bodyweight and in the context of the present invention is directed towardweight loss and the maintenance of weight loss (also called weightmaintenance herein). In addition to controlling body weight, weightmanagement includes controlling parameters related to body weight, forexample, BMI, percent body fat, and waist circumference. For example,weight management for an individual who is overweight or obese can referto losing weight with the goal of keeping weight in a healthier range.Also, for example, weight management for an individual who is overweightor obese can include losing body fat or waist circumference with orwithout the loss of body weight.

The term “maintenance of weight loss” or “weight maintenance” as usedherein includes preventing, reducing, or controlling weight gain afterweight loss. It is well known that weight gain often occurs after weightloss. Weight loss can occur, for example, from dieting, exercising,illness, drug treatment, surgery, or any combination of these methods,but often an individual that has lost weight will regain some or all ofthe lost weight. Therefore, weight maintenance in an individual who haslost weight can include preventing weight gain after weight loss,reducing the amount of weight gained after weight loss, controllingweight gain after weight loss, or slowing the rate of weight gain afterweight loss.

Compounds of the Invention

One aspect of the present invention provides, inter alia, compoundsselected from the following compounds and pharmaceutically acceptablesalts, solvates, and hydrates thereof:

-   3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide;-   3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide;    and-   3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzamide.

One aspect of the present invention provides compounds selected from3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Formula (Ia), Compound 1) and pharmaceutically acceptable salts,solvates, and hydrates thereof.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers and the like. It is understood that the varioustautomeric forms are within the scope of the compounds of the presentinvention.

The compounds of the present invention may be prepared according torelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter in the working Examples. Protection and deprotection may becarried out by procedures generally known in the art (see, for example,Greene, T. W. and Wuts, P. G. M., Protecting Groups in OrganicSynthesis, 3^(rd) Edition, 1999 [Wiley]).

Crystalline Forms of Compound 1

One aspect of the present invention relates to crystalline forms of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Formula (Ia), Compound 1).

Crystalline forms of Compound 1 can be identified by their unique solidstate signature with respect to, for example, differential scanningcalorimetry (DSC), powder X-ray diffraction (PXRD), and other solidstate methods.

Further characterization with respect to water or solvent content ofcrystalline forms can be gauged by any of the following methods forexample, thermogravimetric analysis (TGA), DSC and the like.

For DSC, it is known that the temperatures observed will depend uponsample purity, the rate of temperature change, as well as samplepreparation technique and the particular instrument employed. Thus, thevalues reported herein relating to DSC thermograms can vary by plus orminus about 4° C. The values reported herein relating to DSC thermogramscan also vary by plus or minus about 20 joules per gram.

For PXRD, the relative intensities of the peaks can vary, depending uponthe sample preparation technique, the sample mounting procedure and theparticular instrument employed. Moreover, instrument variation and otherfactors can often affect the °2θ values. Therefore, the peak assignmentsof diffraction patterns can vary by plus or minus 0.2°2θ°.

For TGA, the features reported herein can vary by plus or minus about10° C. For TGA, the features reported herein can also vary by plus orminus about 2% weight change due to, for example, sample variation.

Further characterization with respect to hygroscopicity of thecrystalline forms can be gauged by, for example, dynamic moisturesorption (DMS). The DMS features reported herein can vary by plus orminus about 5% relative humidity. The DMS features reported herein canalso vary by plus or minus about 5% weight change.

Compound 1 (Anhydrous Form)

One aspect of the present invention relates to an anhydrous form of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Compound 1). The physical properties of the crystalline form ofCompound 1 anhydrous form are summarized in the following table.

Compound 1 (Anhydrous Form) PXRD FIG. 6: Peaks of about ≥9.5% relativeintensity at 8.6, 12.2, 13.6, 14.9, 17.5, 18.3, 20.1, 21.1, 21.9, 24.2,24.5, 25.0, 27.2, 30.5, and 31.0 °2θ TGA FIG. 7: Negligible Decrease inweight. DSC FIG. 7: Extrapolated onset temperature: about 148.9° C., andan enthalpy of fusion of 99.5 joules per gram. DMS FIG. 8: Less thanabout 0.35% weight gain at about 90% RH and 25° C.

One aspect of the present invention relates to an anhydrous crystallineform of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Compound 1), wherein the anhydrous crystalline form has a powder X-raydiffraction pattern comprising every combination of one or more peaks,in terms of 2θ, selected from the peaks found in the following table:

Pos. [°2θ] d-spacing [Å] Rel. Int. [%] 8.6 10.3 64.4 8.8 10.0 4.8 12.17.3 5.5 12.2 7.2 10.1 13.6 6.5 85.8 14.9 5.9 13.8 17.2 5.2 5.1 17.5 5.120.7 18.3 4.9 44.5 19.3 4.6 5.3 20.1 4.4 100.0 21.1 4.2 51.0 21.3 4.25.8 21.9 4.1 34.1 23.7 3.8 4.6 24.2 3.7 17.1 24.5 3.6 12.2 25.0 3.6 76.925.9 3.4 6.3 27.2 3.3 57.2 29.4 3.0 7.3 29.8 3.0 5.2 30.5 2.9 9.5 31.02.9 10.5 32.9 2.7 4.4 38.3 2.3 5.0

One aspect of the present invention relates to an anhydrous crystallineform of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide,wherein the anhydrous crystalline form has a powder X-ray diffractionpattern comprising a peak, in terms of 2θ, at 20.1°±0.2°. In someembodiments, the anhydrous crystalline form has a powder X-raydiffraction pattern comprising peaks, in terms of 2θ, at 13.6°±0.2°, and20.1°±0.2°. In some embodiments, the anhydrous crystalline form has apowder X-ray diffraction pattern comprising peaks, in terms of 2θ, at13.6°±0.2°, 20.1°±0.2°, and 25.0°±0.2°. In some embodiments, theanhydrous crystalline form has a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 8.6°±0.2°, 13.6°±0.2°, 20.1°±0.2°,25.0°±0.2°, and 27.2°±0.2°. In some embodiments, the anhydrouscrystalline form has a powder X-ray diffraction pattern comprisingpeaks, in terms of 2θ, at 8.6°±0.2°, 13.6°±0.2°, 18.3°±0.2°, 20.1°±0.2°,21.1°±0.2°, 25.0±0.2°, and 27.2°±0.2°. In some embodiments, theanhydrous crystalline form has a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 8.6°±0.2°, 13.6°±0.2°, 17.5°±0.2°,18.3°±0.2°, 20.1°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 25.0°±0.2°, and27.2°±0.2°. In some embodiments, the anhydrous crystalline form has apowder X-ray diffraction pattern comprising peaks, in terms of 2θ, at8.6°±0.2°, 13.6°±0.2°, 14.9°±0.2° 17.5°±0.2°, 18.3°±0.2°, 20.1°±0.2°,21.1°±0.2°, 21.90°±0.2°, 24.2°±0.2°, 24.5°±0.2°, 25.0°±0.2°, and27.2°±0.2°. In some embodiments, the anhydrous crystalline form has apowder X-ray diffraction pattern substantially as shown in FIG. 6,wherein by “substantially” is meant that the reported peaks can vary byabout ±0.2°±2θ.

In some embodiments, the anhydrous crystalline form has a differentialscanning calorimetry thermogram comprising an endotherm with anextrapolated onset temperature between about 143.9° C. and about 153.9°C. In some embodiments, the anhydrous crystalline form has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature between 145.9° C. and about151.9° C. In some embodiments, the anhydrous crystalline form has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature between about 146.9° C. and about150.9° C. In some embodiments, the anhydrous crystalline form has havinga differential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature between about 147.9° C. and about149.9° C. In some embodiments, the anhydrous crystalline form has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature at about 148.9° C. In someembodiments, the anhydrous crystalline form has a differential scanningcalorimetry thermogram substantially as shown in FIG. 7, wherein by“substantially” is meant that the reported DSC features can vary byabout ±4° C. and that the reported DSC features can vary by about ±20joules per gram.

In some embodiments, the anhydrous crystalline form has athermogravimetric analysis profile showing 1.0% weight loss up to about120° C. In some embodiments, the anhydrous crystalline form has athermogravimetric analysis profile showing 0.5% weight loss up to about120° C. In some embodiments, the anhydrous crystalline form has athermogravimetric analysis profile showing 0.25% weight loss up to about120° C. In some embodiments, the anhydrous crystalline form has athermogravimetric analysis profile showing 0.05% weight loss up to about120° C. In some embodiments, the anhydrous crystalline form has athermogravimetric analysis profile substantially as shown in FIG. 7,wherein by “substantially” is meant that the reported TGA features canvary by about ±10° C., and that that the reported TGA features can varyby about ±2% weight change.

In some embodiments, the anhydrous crystalline form has a dynamicmoisture sorption analysis profile of less than about 0.35% weight gainout to about 90% RH at about 25° C. In some embodiments, the anhydrouscrystalline form has a dynamic moisture sorption analysis profilesubstantially as shown in FIG. 8, wherein by “substantially” is meantthat the reported DMS features can vary by plus or minus about 5% weightchange.

One aspect of the present invention relates to the anhydrous crystallineform having:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 13.6°±0.2° and 20.1°±0.2°;

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature between about 143.9° C.and about 153.9° C.; and/or

3) a thermogravimetric analysis profile showing 0.5% weight loss up toabout 120° C.

One aspect of the present invention relates to the anhydrous crystallineform having:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 13.6°±0.2°, 20.1°±0.2°, and 25.0°±0.2°;

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature between about 145.9° C.and about 151.9° C.; and/or

3) a thermogravimetric analysis profile showing 0.25% weight loss up toabout 120° C.

One aspect of the present invention relates to the anhydrous crystallineform having:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.6°±0.2°, 13.6°±0.2°, 20.1°±0.2°, 25.0°±0.2°, and 27.2°±0.2°;

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature between about 146.9° C.and about 150.9° C.; and/or

3) a thermogravimetric analysis profile showing 0.05% weight loss up toabout 120° C.

One aspect of the present invention relates to the anhydrous crystallineform having:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.6°±0.2°, 13.6°±0.2°, 18.3°±0.2°, 20.1°±0.2°, 21.1°±0.2°,25.0°±0.2°, and 27.2°±0.2°.

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature between about 147.9° C.and about 149.9° C.; and/or

3) a thermogravimetric analysis profile showing 0.05% weight loss up toabout 120° C.

One aspect of the present invention relates to the anhydrous crystallineform having:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.6°±0.2°, 13.6°±0.2°, 17.5°±0.2°, 18.30°±0.2°, 20.1°±0.2°,21.1°±0.2°, 21.9°±0.2°, 25.0°±0.2° and 27.2°±0.2°;

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature at about 147.9° C. andabout 149.9° C.; and/or

3) a thermogravimetric analysis profile showing 0.05% weight loss up toabout 120° C.

One aspect of the present invention relates to the anhydrous crystallineform having:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.6°±0.2°, 13.6°±0.2°, 14.9°±0.2°, 17.5°±0.2°, 18.3°±0.2°,20.1°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 24.2°±0.2°, 24.5°±0.2°, 25.0°±0.2°,and 27.2°±0.2°;

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature at about 148.9° C.;and/or

3) a thermogravimetric analysis profile showing 0.05% weight loss up toabout 120° C.

One aspect of the present invention relates to the anhydrous crystallineform having:

1) a powder X-ray diffraction pattern substantially as shown in FIG. 6;

2) a differential scanning calorimetry thermogram substantially as shownin FIG. 7;

3) a thermogravimetric analysis profile substantially as shown in FIG.7; and/or

4) a dynamic moisture sorption analysis profile substantially as shownin FIG. 8.

Certain Embodiments: Compositions, Methods, Indications, PharmaceuticalProducts, Combinations, and Uses of Compounds of the Present Invention

In addition to the foregoing, without limitation, certain otherembodiments are described and provided below.

Certain Compositions of the Present Invention:

One aspect of the present invention pertains to compositions comprisinga compound of the present invention.

The term “composition” refers to at least one compound of the inventionin combination with at least one other component. It is understood, thatthe amount of a compound of the present invention in a composition canbe any amount ranging from less than 100.00% to greater than 0.00%.Examples of compositions include, but are not limited to, a referencestandard comprising a compound of the present invention (e.g., for usein method development, in-process testing, and the like); bulk APT(i.e., Active Pharmaceutical Ingredient) of a compound of the presentinvention (e.g., for use in formulating a pharmaceutical composition); acombined preparation (i.e., a compound of the present invention incombination with a pharmaceutical/therapeutic agent or agents); abiological sample comprising a compound of the present invention (e.g.,for use in or obtained from a patient, an animal, a pharmacokineticstudy, ADME study, LADME study, and the like); a reaction mixturecomprising a compound of the present invention, such as, a reactionmixture as described in any of the Examples herein; a manufacturingreaction mixture comprising a compound of the present invention incombination with one or more components such as solvents, reactants,side-products, etc.; and the like. It is understood that pharmaceuticalcompositions are a specific subset of compositions.

One aspect of the present invention pertains to compositions comprisinga compound of the present invention and a pharmaceutically acceptablecarrier.

One aspect of the present invention pertains to methods for preparing acomposition comprising the step of admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to pharmaceutical productsselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention.

One aspect of the present invention pertains to compositions comprisinga compound of the present invention and a second pharmaceutical agent.

In any of the embodiments that recites the terms “a pharmaceuticalagent” and/or “a second pharmaceutical agent”, it is appreciated thatthese terms in some aspects be further limited to a pharmaceutical agentor a second pharmaceutical agent that is not a Compound of Formula (Ia).It is understood that the terms “a pharmaceutical agent” and “a secondpharmaceutical agent” may refer to a pharmaceutical agent or a secondpharmaceutical agent that is not detectable or has an EC₅₀ that isgreater than a value selected from: 50 μM, 10 μM, 1 μM, and 0.1 μM in aGPR119 receptor activity assay as described in Example 5.

One aspect of the present invention pertains to methods for preparing acomposition comprising the step of admixing a compound of the presentinvention and a second pharmaceutical agent.

One aspect of the present invention pertains to compositions comprisinga compound of the present invention, a second pharmaceutical agent, anda pharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for preparing acomposition comprising the step of admixing a compound of the presentinvention, a second pharmaceutical agent, and a pharmaceuticallyacceptable carrier.

The present invention further provides pharmaceutical compositions.Accordingly, one aspect of the present invention pertains topharmaceutical compositions comprising a compound of the presentinvention and a pharmaceutically acceptable carrier. One aspect of thepresent invention pertains to methods for preparing a compositioncomprising the step of admixing a compound of the present invention anda pharmaceutically acceptable carrier. One aspect of the presentinvention pertains to pharmaceutical compositions comprising a compoundof the present invention, a second pharmaceutical agent, and apharmaceutically acceptable carrier. One aspect of the present inventionpertains to methods for preparing a composition comprising the step ofadmixing a compound of the present invention, a second pharmaceuticalagent, and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention and a second pharmaceutical agent.

One aspect of the present invention pertains to compositions obtained bythe methods of the present invention as described herein.

Certain Methods, Pharmaceutical Products, Combinations, and Uses of thePresent Invention

One aspect of the present invention pertains to methods for modulatingthe activity of a GPR119 receptor, comprising administering to anindividual in need thereof: a therapeutically effective amount of acompound of the present invention; a composition of the presentinvention; or a pharmaceutical product of the present invention.

One aspect of the present invention pertains to methods for thetreatment of a disorder selected from: a GPR119-receptor-relateddisorder; a condition ameliorated by increasing secretion of anincretin; a condition ameliorated by increasing a blood incretin level;a condition characterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity; in an individual; comprisingadministering to the individual in need thereof: a therapeuticallyeffective amount of a compound of the present invention; a compositionof the present invention; or a pharmaceutical product of the presentinvention.

One aspect of the present invention pertains to methods for increasingthe secretion of an incretin in an individual or increasing a bloodincretin level in an individual, comprising administering to theindividual in need thereof: a therapeutically effective amount of acompound of the present invention; a composition of the presentinvention; or a pharmaceutical product of the present invention.

One aspect of the present invention pertains to methods for thetreatment of a disorder selected from: a GPR119-receptor-relateddisorder; a condition ameliorated by increasing secretion of anincretin; a condition ameliorated by increasing a blood incretin level;a condition characterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity; in an individual; comprisingprescribing to the individual in need thereof: a therapeuticallyeffective amount of a compound of the present invention; a compositionof the present invention; or a pharmaceutical product of the presentinvention.

Example 6 shows that Compound 1 is metabolized to Compound 2 andCompound 3. Accordingly, one aspect of the present invention pertains tomethods for increasing the secretion of an incretin in an individual orincreasing a blood incretin level in an individual, comprisingadministering to the individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention, wherein thecompound is generated as a result of a metabolic chemical reaction of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimiethylbenzamide(Compound 1), or a pharmaceutically acceptable salt thereof. Anotheraspect of the present invention pertains to methods for the treatment ofa disorder selected from: a GPR119-receptor-related disorder; acondition ameliorated by increasing secretion of an incretin; acondition ameliorated by increasing a blood incretin level; a conditioncharacterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity; in an individual; comprisingadministering to the individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention, wherein thecompound is generated as a result of a metabolic chemical reaction of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Compound 1), or a pharmaceutically acceptable salt thereof. In someembodiments, the compound is3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide(Compound 2), or a pharmaceutically acceptable salt thereof. In someembodiments, the compound is3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzamide(Compound 3), or a pharmaceutically acceptable salt thereof.

One aspect of the present invention pertains to the use of a compound ofthe present invention; or a composition of the present invention; in themanufacture of a medicament for modulating the activity of a GPR119receptor in an individual.

One aspect of the present invention pertains to the use of a compound ofthe present invention; or a composition of the present invention; in themanufacture of a medicament for increasing the secretion of an incretinin an individual or increasing a blood incretin level in an individual.

One aspect of the present invention pertains to the use of a compound ofthe present invention; or a composition of the present invention; in themanufacture of a medicament for the treating a disorder in anindividual, wherein the disorder is selected from: aGPR119-receptor-related disorder; a condition ameliorated by increasingsecretion of an incretin; a condition ameliorated by increasing a bloodincretin level; a condition characterized by low bone mass; aneurological disorder; a metabolic-related disorder; and obesity.

One aspect of the present invention pertains to a compound of thepresent invention; a composition of the present invention; or apharmaceutical product of the present invention; for use in a method oftreatment of the human or animal body by therapy.

One aspect of the present invention pertains to a compound of thepresent invention; a composition of the present invention; or apharmaceutical product of the present invention; for use in a method ofmodulating the activity of a GPR119 receptor in an individual.

One aspect of the present invention pertains to a compound of thepresent invention; a composition of the present invention; or apharmaceutical product of the present invention; for use in a method ofincreasing the secretion of an incretin in an individual or increasing ablood incretin level in an individual.

One aspect of the present invention pertains to a compound of thepresent invention; a composition of the present invention; or apharmaceutical product of the present invention; for use in a method oftreating a disorder in an individual, wherein the disorder is selectedfrom: a GPR119-receptor-related disorder; a condition ameliorated byincreasing secretion of an incretin; a condition ameliorated byincreasing a blood incretin level; a condition characterized by low bonemass; a neurological disorder; a metabolic-related disorder; andobesity.

One aspect of the present invention pertains to a compound of thepresent invention for use in a method of treatment of the human oranimal body by therapy, wherein the compound is generated as a result ofa metabolic chemical reaction of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide,or a pharmaceutically acceptable salt thereof.

One aspect of the present invention pertains to a compound of thepresent invention for use in a method of increasing the secretion of anincretin in an individual or increasing a blood incretin level in anindividual, wherein the compound is generated as a result of a metabolicchemical reaction of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide,or a pharmaceutically acceptable salt thereof.

One aspect of the present invention pertains to a compound of thepresent invention for use in a method of treating a disorder in anindividual, wherein the compound is generated as a result of a metabolicchemical reaction of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide,or a pharmaceutically acceptable salt thereof, and the disorder isselected from: a GPR119-receptor-related disorder; a conditionameliorated by increasing secretion of an incretin; a conditionameliorated by increasing a blood incretin level; a conditioncharacterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention; for use in a method of treatment ofthe human or animal body by therapy.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention; for use in a method of modulating theactivity of a GPR119 receptor in an individual.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound according to claim 1; for use in a method of increasing thesecretion of an incretin in an individual or increasing a blood incretinlevel in an individual.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention for use in a method of treating adisorder selected from: a GPR119-receptor-related disorder; a conditionameliorated by increasing secretion of an incretin; a conditionameliorated by increasing a blood incretin level; a conditioncharacterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity; in an individual.

One aspect of the present invention pertains to methods for modulatingthe activity of a GPR119 receptor, comprising administering to anindividual in need thereof, a compound of the present invention incombination with a second pharmaceutical agent.

One aspect of the present invention pertains to methods for agonizing aGPR119 receptor, comprising administering to an individual in needthereof, a compound of the present invention in combination with asecond pharmaceutical agent.

One aspect of the present invention pertains to methods for increasingthe secretion of an incretin in an individual or increasing a bloodincretin level in an individual, comprising administering to theindividual in need thereof, a compound of the present invention incombination with a second pharmaceutical agent.

One aspect of the present invention pertains to methods for increasingthe secretion of an incretin in an individual or increasing a bloodincretin level in an individual, comprising prescribing to theindividual in need thereof, a compound of the present invention incombination with a second pharmaceutical agent.

One aspect of the present invention pertains to methods for thetreatment of a disorder selected from: a GPR119-receptor-relateddisorder; a condition ameliorated by increasing secretion of anincretin; a condition ameliorated by increasing a blood incretin level;a condition characterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity; in an individual; comprisingadministering to the individual in need thereof, a compound of thepresent invention in combination with a second pharmaceutical agent.

One aspect of the present invention pertains to methods for thetreatment of a disorder selected from: a GPR119-receptor-relateddisorder; a condition ameliorated by increasing secretion of anincretin; a condition ameliorated by increasing a blood incretin level;a condition characterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity; in an individual; comprisingprescribing to the individual in need thereof, a compound of the presentinvention in combination with a second pharmaceutical agent.

One aspect of the present invention pertains to the use of a compound ofthe present invention in combination with a second pharmaceutical agentin the manufacture of a medicament for modulating the activity of aGPR119 receptor in an individual.

One aspect of the present invention pertains to the use of a compound ofthe present invention in combination with a second pharmaceutical agentin the manufacture of a medicament for agonizing a GPR119 receptor in anindividual.

One aspect of the present invention pertains to the use of a compound ofthe present invention in combination with a second pharmaceutical agentin the manufacture of a medicament for increasing the secretion of anincretin in an individual or increasing a blood incretin level in anindividual.

One aspect of the present invention pertains to the use of a compound ofthe present invention in combination with a second pharmaceutical agent,in the manufacture of a medicament for the treatment of a disorderselected from: a GPR119-receptor-related disorder; a conditionameliorated by increasing secretion of an incretin; a conditionameliorated by increasing a blood incretin level; a conditioncharacterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity.

One aspect of the present invention pertains to the use of apharmaceutical agent in combination with a compound of the presentinvention, in the manufacture of a medicament for modulating theactivity of a GPR119 receptor in an individual.

One aspect of the present invention pertains to the use of apharmaceutical agent in combination with a compound of the presentinvention, in the manufacture of a medicament for agonizing a GPR119receptor in an individual.

One aspect of the present invention pertains to the use of apharmaceutical agent in combination with a compound of the presentinvention, in the manufacture of a medicament for increasing thesecretion of an incretin in an individual or increasing a blood incretinlevel in an individual.

One aspect of the present invention pertains to the use of apharmaceutical agent in combination with a compound of the presentinvention, in the manufacture of a medicament for the treatment of adisorder selected from: a GPR119-receptor-related disorder; a conditionameliorated by increasing secretion of an incretin; a conditionameliorated by increasing a blood incretin level; a conditioncharacterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity.

One aspect of the present invention pertains to a compound of thepresent invention for use in combination with a second pharmaceuticalagent in a method of treatment of the human or animal body by therapy.

One aspect of the present invention pertains to a compound of thepresent invention for use in combination with a second pharmaceuticalagent in a method of modulating the activity of a GPR119 receptor in anindividual.

One aspect of the present invention pertains to a compound of thepresent invention for use in combination with a second pharmaceuticalagent in a method of agonizing a GPR119 receptor in an individual.

One aspect of the present invention pertains to a compound of thepresent invention for use in combination with a second pharmaceuticalagent for increasing the secretion of an incretin in an individual orincreasing a blood incretin level in an individual.

One aspect of the present invention pertains to a compound of thepresent invention for use in combination with a second pharmaceuticalagent in a method of treating a disorder selected from: aGPR119-receptor-related disorder; a condition ameliorated by increasingsecretion of an incretin; a condition ameliorated by increasing a bloodincretin level; a condition characterized by low bone mass; aneurological disorder; a metabolic-related disorder; and obesity; in anindividual.

One aspect of the present invention pertains to a pharmaceutical agentfor use in combination with a compound of the present invention, in amethod of treatment of the human or animal body by therapy.

One aspect of the present invention pertains to a pharmaceutical agentfor use in combination with a compound of the present invention, inmodulating the activity of a GPR119 receptor in an individual.

One aspect of the present invention pertains to a pharmaceutical agentfor use in combination with a compound of the present invention, in amethod of agonizing a GPR119 receptor in an individual.

One aspect of the present invention pertains to a pharmaceutical agentin combination with a compound of the present invention, for increasingthe secretion of an incretin in an individual or increasing a bloodincretin level in an individual.

One aspect of the present invention pertains to a pharmaceutical agentfor use in combination with a compound of the present invention, in amethod of treating a disorder selected from: a GPR119-receptor-relateddisorder; a condition ameliorated by increasing secretion of anincretin; a condition ameliorated by increasing a blood incretin level;a condition characterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity; in an individual.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention and a second pharmaceutical agent; foruse in a method of treatment of the human or animal body by therapy.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention and a second pharmaceutical agent; foruse in a method of modulating the activity of a GPR119 receptor in anindividual.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention and a second pharmaceutical agent; foruse in a method of agonizing a GPR119 receptor in an individual.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention and a second pharmaceutical agent; foruse in a method of increasing the secretion of an incretin in anindividual or increasing a blood incretin level in an individual.

One aspect of the present invention pertains to a pharmaceutical productselected from: a pharmaceutical composition, a formulation, a dosageform, a combined preparation, a twin pack, and a kit; comprising acompound of the present invention and a second pharmaceutical agent foruse in a method of treating a disorder selected from: aGPR119-receptor-related disorder; a condition ameliorated by increasingsecretion of an incretin; a condition ameliorated by increasing a bloodincretin level; a condition characterized by low bone mass; aneurological disorder; a metabolic-related disorder; and obesity; in anindividual.

One aspect of the present invention pertains to compounds, methods,compositions, uses of compounds, pharmaceutical agents, andpharmaceutical products, each as described herein, wherein modulatingthe activity of a GPR119 receptor is agonizing the GPR119 receptor in anindividual.

One aspect of the present invention pertains to compounds, methods,compositions, uses of compounds, pharmaceutical agents, andpharmaceutical products, each as described herein, wherein modulatingthe activity of a GPR119 receptor is increasing the secretion of anincretin in an individual.

One aspect of the present invention pertains to compounds, methods,compositions, uses of compounds, pharmaceutical agents, andpharmaceutical products, each as described herein, wherein modulatingthe activity of a GPR119 receptor is increasing a blood incretin levelin an individual.

One aspect of the present invention pertains to compounds, methods,compositions, uses of compounds, pharmaceutical agents, andpharmaceutical products, each as described herein, wherein modulatingthe activity of a GPR119 receptor treating a disorder, wherein thedisorder is selected from: a GPR119-receptor-related disorder; acondition ameliorated by increasing secretion of an incretin; acondition ameliorated by increasing a blood incretin level; a conditioncharacterized by low bone mass; a neurological disorder; ametabolic-related disorder; and obesity.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide,an alpha-glucosidase inhibitor, a sulfonylurca, an SGLT2 inhibitor, anda meglitinide. In some embodiments, the pharmaceutical agent or thesecond pharmaceutical agent is selected from: sitagliptin, vildagliptin,saxagliptin, alogliptin, linagliptin, phenformin, metformin, buformin,acarbose, miglitol, voglibose, tolbutamide, acetohexamide, tolazamide,chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide,dapaglillozin, remogliflozin, and scrgliflozin.

In some embodiments, the disorder is type 2 diabetes. In someembodiments, the disorder is hyperglycemia. In some embodiments, thedisorder is hyperlipidemia. In some embodiments, the disorder ishypertriglyceridemia. In some embodiments, the disorder is type 1diabetes. In some embodiments, the disorder is dyslipidemia. In someembodiments, the disorder is syndrome X. In some embodiments, thedisorder is obesity.

In some embodiments, the pharmaceutical product comprises apharmaceutical composition. In some embodiments, the pharmaceuticalproduct comprises a formulation. In some embodiments, the pharmaceuticalproduct comprises a dosage form. In some embodiments, the pharmaceuticalproduct comprises a combined preparation. In some embodiments, thepharmaceutical product comprises a twin pack. In some embodiments, thepharmaceutical product comprises a kit.

In some embodiments, the compound and the second pharmaceutical agentare administered simultaneously, separately, or sequentially. In someembodiments, the compound and the pharmaceutical agent or secondpharmaceutical agent are administered simultaneously.

In some embodiments, the compound and the pharmaceutical agent or secondpharmaceutical agent are administered separately. In some embodiments,the compound and the pharmaceutical agent or second pharmaceutical agentare administered sequentially.

In some embodiments, the incretin is GLP-1. In some embodiments, theincretin is GIP. In some embodiments, the incretin is PYY.

One aspect of the present invention pertains to compounds, methods,compositions, uses of compounds, pharmaceutical agents, andpharmaceutical products wherein the amount of the compound of thepresent invention and the amount of the second pharmaceutical agent whenadministered alone are substantially therapeutically ineffective (i.e.,a sub-therapeutic amount); however the amount of the compound of thepresent invention and the amount of the second pharmaceutical agent whenadministered simultaneously, separately, or sequentially, are sufficientto be therapeutically effective at treating the disorder.

In some embodiments, the compound and the pharmaceutical agent or thesecond pharmaceutical agent are provided in amounts which give asynergistic effect in treating the disorder. In some embodiments, theamount of the compound alone is substantially therapeuticallyineffective at treating the disorder. In some embodiments, the amount ofthe pharmaceutical agent alone or the second pharmaceutical agent aloneis substantially therapeutically ineffective at treating the disorder.

One aspect of the present invention pertains to methods for preparing apharmaceutical product, as described herein, comprising: mixing thecompound of the present invention with a first pharmaceuticallyacceptable carrier to prepare a compound dosage form, mixing the secondpharmaceutical agent with a second pharmaceutically acceptable carrierto prepare a second pharmaceutical agent dosage form, and providing thecompound dosage form and the second pharmaceutical agent dosage form ina combined dosage form for simultaneous, separate, or sequential use.

In some embodiments, the first pharmaceutically acceptable carrier andthe second pharmaceutically acceptable carrier are different. In someembodiments, the different pharmaceutically acceptable carriers aresuitable for administration by the same route or different routes. Insome embodiments, the first pharmaceutically acceptable carrier and thesecond pharmaceutically acceptable carrier are substantially the same.In some embodiments, the substantially the same pharmaceuticallyacceptable carriers are suitable for administration by the same route.In some embodiments, the substantially the same pharmaceuticallyacceptable carriers are suitable for oral administration.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide,an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, anSGLT2 inhibitor, a meglitinide, a thiazolidinedione, and ananti-diabetic peptide analogue. In some embodiments, the pharmaceuticalagent or the second pharmaceutical agent is selected from: a DPP-IVinhibitor, a biguanide, an alpha-glucosidase inhibitor, a sulfonylurea,an SGLT2 inhibitor, and a meglitinide. In some embodiments, thepharmaceutical agent or the second pharmaceutical agent is selectedfrom: a DPP-IV inhibitor, a biguanide, and an alpha-glucosidaseinhibitor. In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a DPP-IV inhibitor. In some embodiments, thepharmaceutical agent or the second pharmaceutical agent is a biguanide.In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is an alpha-glucosidase inhibitor.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea. In some embodiments, thepharmaceutical agent or the second pharmaceutical agent is an SGLT2inhibitor. In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a meglitinide. In some embodiments, thepharmaceutical agent or the second pharmaceutical agent is a biguanideselected from the following compounds and pharmaceutically acceptablesalts, solvates, and hydrates thereof: metformin, phenformin, buformin,and proguanil. In some embodiments, the pharmaceutical agent or thesecond pharmaceutical agent is an alpha-glucosidase inhibitor selectedfrom the following compounds and pharmaceutically acceptable salts,solvates, and hydrates thereof: acarbose, miglitol, and voglibose.

One aspect of the present invention pertains to methods for weightmanagement, comprising administering to an individual in need thereof, acompound of the present invention in combination with a secondpharmaceutical agent, such as any agent described herein.

In some embodiments, the weight management comprises weight loss. Insome embodiments, the weight management comprises maintenance of weightloss. In some embodiments, the weight management further comprises areduced-calorie diet. In some embodiments, the weight management furthercomprises a program of regular exercise. In some embodiments, the weightmanagement further comprises both a reduced-calorie diet and a programof regular exercise.

In some embodiments, the individual in need of weight management is apatient with an initial body mass of index ≥40 kg/m²; ≥39 kg/m²; ≥38kg/m²; ≥37 kg/m²; ≥36 kg/m²; ≥35 kg/m²; ≥34 kg/m²; ≥33 kg/m²; ≥32 kg/m²;≥31 kg/m²; ≥30 kg/m²; ≥29 kg/m²; ≥28 kg/m²; ≥27 kg/m²; ≥26 kg/m²; ≥25kg/m²; ≥24 kg/m²; ≥23 kg/m²; ≥22 kg/m²; ≥21 kg/m²; or ≥20 kg/m²; and thepatient optionally has at least one or at least two weight relatedcomorbid condition(s).

In some embodiments, the comorbid condition(s) when present are selectedfrom: hypertension, dyslipidemia, cardiovascular disease, glucoseintolerance, and sleep apnea.

Certain Indications of the Present Invention

In the context of the present invention, a compound as described hereinor a pharmaceutical composition thereof can be utilized for modulatingthe activity of GPR119-receptor-related diseases, conditions and/ordisorders as described herein.

In some embodiments, modulating the activity of the GPR119 receptorincludes the treatment of a GPR119-receptor-related disorder. In someembodiments, the GPR119-receptor-related disorder is a conditionameliorated by increasing secretion of an incretin. In some embodiments,the GPR119-receptor-related disorder is a condition ameliorated byincreasing a blood incretin level. In some embodiments, the incretin isGLP-1. In some embodiments, the incretin is GIP. In some embodiments,the incretin is PYY.

In some embodiments, the GPR119-receptor-related disorder is a conditioncharacterized by low bone mass. In some embodiments, theGPR119-receptor-related disorder is a neurological disorder. In someembodiments, the GPR119-receptor-related disorder is a metabolic-relateddisorder. In some embodiments, the GPR119-receptor-related disorder istype 2 diabetes. In some embodiments, the GPR119-receptor-relateddisorder is obesity

Some embodiments of the present invention include every combination ofone or more conditions characterized by low bone mass selected from:osteopenia, osteoporosis, rheumatoid arthritis, ostcoarthritis,periodontal disease, alveolar bone loss, ostcotomy bone loss, childhoodidiopathic bone loss, Paget's disease, bone loss due to metastaticcancer, osteolytic lesions, curvature of the spine, and loss of height.

In some embodiments, the neurological disorder selected from: stroke andParkinson's disease.

Some embodiments of the present invention include every combination ofone or more metabolic-related disorders selected from: type 1 diabetes,type 2 diabetes mellitus, and conditions associated therewith, such as,but not limited to, coronary heart disease, ischemic stroke, restenosisafter angioplasty, peripheral vascular disease, intermittentclaudication, myocardial infarction (e.g. necrosis and apoptosis),dyslipidemia, postprandial lipemia, conditions of impaired glucosetolerance (IGT), conditions of impaired fasting plasma glucose,metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension,congestive heart failure, left ventricular hypertrophy, peripheralarterial disease, diabetic retinopathy, macular degeneration, cataract,diabetic nephropathy, glomerulosclerosis, chronic renal failure,diabetic neuropathy, metabolic syndrome, syndrome X, premenstrualsyndrome, coronary heart disease, angina pectoris, thrombosis,atherosclerosis, myocardial infarction, transient ischemic attacks,stroke, vascular restenosis, hyperglycemia, hyperinsulinemia,hyperlipidemia, hypertriglyceridemia, insulin resistance, impairedglucose metabolism, erectile dysfunction, skin and connective tissuedisorders, foot ulcerations and ulcerative colitis, endothelialdysfunction and impaired vascular compliance.

Some embodiments of the present invention include every combination ofone or more metabolic-related disorders selected from: diabetes, type 1diabetes, type 2 diabetes, inadequate glucose tolerance, impairedglucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, dyslipidemia,atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cellinsufficiency, enteroendocrine cell insufficiency, glycosuria, metabolicacidosis, a cataract, diabetic nephropathy, diabetic neuropathy,peripheral neuropathy, diabetic coronary artery disease, diabeticcerebrovascular disease, diabetic peripheral vascular disease, diabeticretinopathy, metabolic syndrome, a condition related to diabetes,myocardial infarction, learning impairment, memory impairment, aneurodegenerative disorder, a condition ameliorated by increasing ablood GLP-1 level in an individual with a neurodegenerative disorder,excitotoxic brain damage caused by severe epileptic seizures,Alzheimer's disease, Parkinson's disease, Huntington's disease,prion-associated disease, stroke, motor-neuron disease, traumatic braininjury, spinal cord injury, and obesity.

In some embodiments, the disorder is type 2 diabetes. In someembodiments, the disorder is hyperglycemia. In some embodiments, thedisorder is hyperlipidemia. In some embodiments, the disorder ishypertriglyceridemia. In some embodiments, the disorder is type 1diabetes. In some embodiments, the disorder is dyslipidemia. In someembodiments, the disorder is syndrome X. In some embodiments, thedisorder is obesity. In some embodiments, the disorder is metabolicsyndrome.

The term “metabolic syndrome” as used herein, refers to a set of riskfactors that make a patient more susceptible to cardiovascular diseaseand/or type 2 diabetes. An individual is referred to having metabolicsyndrome if the individual simultaneously has three or more of thefollowing five risk factors as set forth by the American HeartAssociation and the National Heart, Lung, and Blood Institute: (1)Elevated waist circumference: Men—≥40 inches (102 cm), Women—≥35 inches(88 cm); (2) Elevated triglycerides: ≥150 mg/dL; (3) Reduced HDI,(“good”) cholesterol: Men—<40 mg/dL, Women—<50 mg/dL; (4) Elevated bloodpressure: ≥130/85 mm Hg; and (5) Elevated fasting glucose: ≥100 mg/dL.

Formulations and Compositions

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions and syrups. Alternatively, the oral preparations maybe in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20^(th) Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro et al.).

While it is possible that, for use in the prophylaxis or treatment, acompound of the invention may, in an alternative use, be administered asa raw or pure chemical, however, it is preferable to present thecompound or active ingredient as a pharmaceutical formulation orcomposition further comprising a pharmaceutically acceptable carrier.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, subcutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with minimal degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a solvate, hydrate orphysiologically functional derivative thereof can be used as activeingredients in pharmaceutical compositions, specifically as GPR119receptor modulators. The term “active ingredient”, defined in thecontext of a “pharmaceutical composition”, refers to a component of apharmaceutical composition that provides the primary pharmacologicaleffect, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits and as is customary and is known to the physician, itis to be tailored to the individual conditions in each individual case.It depends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxisconducted or on whether further active compounds are administered inaddition to the compounds of the present invention. Representative dosesof the present invention include, but not limited to, about 0.001 mg toabout 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about25 mg. Multiple doses may be administered during the day, especiallywhen relatively large amounts are deemed to be needed, for example 2, 3or 4 doses. Depending on the individual and as deemed appropriate fromthe patient's physician or caregiver it may be necessary to deviateupward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, on whether anacute or chronic disease state is being treated or prophylaxis conductedor on whether further active compounds are administered in addition tothe compounds of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4 part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt, solvate, or hydrate of a compound ofthe invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5% to about 90% of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, tale, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter and the like. The term “preparation”refers to the formulation of the active compound with encapsulatingmaterial as carrier providing a capsule in which the active component,with or without carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets and lozenges can be used assolid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents and thelike.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of thepresent invention or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the present invention as an aerosol can be prepared byprocesses well known to the person skilled in the art. For theirpreparation, for example, solutions or dispersions of the compounds ofthe present invention in water, water/alcohol mixtures or suitablesaline solutions can be employed using customary additives, for examplebenzyl alcohol or other suitable preservatives, absorption enhancers forincreasing the bioavailability, solubilizers, dispersants and othersand, if appropriate, customary propellants, for example include carbondioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane,or dichlorotetrafluoroethane; and the like. The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric,tartaric, oxalic, p-toluenesulfonic and the like. Certain compounds ofthe present invention which contain a carboxylic acid functional groupmay optionally exist as pharmaceutically acceptable salts containingnon-toxic, pharmaceutically acceptable metal cations and cations derivedfrom organic bases. Representative metals include, but are not limitedto, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc andthe like. In some embodiments the pharmaceutically acceptable metal issodium. Representative organic bases include, but are not limited to,benzathine (N¹,N²-dibenzylethane-1,2-diamine), chloroprocaine(2-(diethylamino)ethyl 4-(chloroamino)benzoate), choline,diethanolamine, ethylenediamine, meglumine((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol), procaine(2-(diethylamino)ethyl 4-aminobenzoate), and the like. Certainpharmaceutically acceptable salts are listed in Berge, et al., Journalof Pharmaceutical Sciences, 66:1-19 (1977).

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compounds of the present invention may also be administered via a rapiddissolving or a slow release composition, wherein the compositionincludes a biodegradable rapid dissolving or slow release carrier (suchas a polymer carrier and the like) and a compound of the invention.Rapid dissolving or slow release carriers are well known in the art andare used to form complexes that capture therein an active compound(s)and either rapidly or slowly degrade/dissolve in a suitable environment(e.g., aqueous, acidic, basic, etc). Such particles are useful becausethey degrade/dissolve in body fluids and release the active compound(s)therein. The particle size of a compound of the present invention,carrier or any excipient used in such a composition may be optimallyadjusted using techniques known to those of ordinary skill in the art.

Particle size can play an important role in formulation. Reducing thesize of the particles can be used to modify the physicalcharacteristics. Particle size reduction increases both the number ofparticles and the amount of surface area per unit of volume. Theincreased surface area can improve the rate of solvation and thereforesolubility. In addition, particle size reduction can improvegastrointestinal absorption for less soluble compounds. Particle sizereduction can be obtained by any of the methods know in the art, forexample, precipitation/crystallization, comminution (size reduction by amechanical process), and the like, see for example Remington, TheScience and Practice of Pharmacy, 20^(th) Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro et al.).

Compounds of the present invention can be converted to “pro-drugs.” Theterm “pro-drugs” refers to compounds that have been modified withspecific chemical groups known in the art and when administered into anindividual these groups undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Inone general aspect, the “pro-drug” approach is utilized to facilitateoral absorption. A thorough discussion is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S.Symposium Series; and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, together with at least one knownpharmaceutical agent as described herein and a pharmaceuticallyacceptable carrier.

It is noted that when the GPR119 receptor modulators are utilized asactive ingredients in pharmaceutical compositions, these are notintended for use in humans only, but in non-human mammals as well.Recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as GPR119receptor modulators, for the treatment of a GPR119 receptor-associateddisease or disorder in companionship animals (e.g., cats, dogs, etc.)and in livestock animals (e.g., horses, cows, etc.). Those of ordinaryskill in the art are readily credited with understanding the utility ofsuch compounds in such settings.

Hydrates and Solvates

It is understood that when the phrase “pharmaceutically acceptablesalts, solvates, and hydrates” or the phrase “pharmaceuticallyacceptable salt, solvate, or hydrate” is used when referring tocompounds described herein, it embraces pharmaceutically acceptablesolvates and/or hydrates of the compounds, pharmaceutically acceptablesalts of the compounds, as well as pharmaceutically acceptable solvatesand/or hydrates of pharmaceutically acceptable salts of the compounds.It is also understood that when the phrase “pharmaceutically acceptablesolvates and hydrates” or the phrase “pharmaceutically acceptablesolvate or hydrate” is used when referring to salts described herein, itembraces pharmaceutically acceptable solvates and/or hydrates of suchsalts.

It will be apparent to those skilled in the art that the dosage formsdescribed herein may comprise, as the active component, either acompound described herein or a pharmaceutically acceptable salt or as apharmaceutically acceptable solvate or hydrate thereof. Moreover,various hydrates and solvates of the compounds described herein andtheir salts will find use as intermediates in the manufacture ofpharmaceutical compositions. Typical procedures for making andidentifying suitable hydrates and solvates, outside those mentionedherein, are well known to those in the art; see for example, pages202-209 of K. J. Guillory, “Generation of Polymorphs, Hydrates,Solvates, and Amorphous Solids,” in: Polymorphism in PharmaceuticalSolids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York,1999. Accordingly, one aspect of the present invention pertains tomethods of administering hydrates and solvates of compounds describedherein and/or their pharmaceutical acceptable salts, that can beisolated and characterized by methods known in the art, such as,thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infraredspectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration,high resolution X-ray diffraction, and the like. There are severalcommercial entities that provide quick and efficient services foridentifying solvates and hydrates on a routine basis. Example companiesoffering these services include Wilmington PharmaTech (Wilmington,Del.), Avantium Technologies (Amsterdam) and Aptuit (Greenwich, Conn.).

Polymorphs and Pseudopolymorphs

Polymorphism is the ability of a substance to exist as two or morecrystalline phases that have different arrangements and/or conformationsof the molecules in the crystal lattice. Polymorphs show the sameproperties in the liquid or gaseous state but they behave differently inthe solid state.

Besides single-component polymorphs, drugs can also exist as salts andother multicomponent crystalline phases. For example, solvates andhydrates may contain an API host and either solvent or water molecules,respectively, as guests. Analogously, when the guest compound is a solidat room temperature, the resulting form is often called a cocrystal.Salts, solvates, hydrates, and cocrystals may show polymorphism as well.Crystalline phases that share the same API host, but differ with respectto their guests, may be referred to as pseudopolymorphs of one another.

Solvates contain molecules of the solvent of crystallization in adefinite crystal lattice. Solvates, in which the solvent ofcrystallization is water, are termed hydrates. Because water is aconstituent of the atmosphere, hydrates of drugs may be formed rathereasily. By way of example, Stahly recently published a polymorph screenof 245 compounds consisting of a “wide variety of structural types” thatrevealed about 90% of the compounds exhibited multiple solid forms.Overall, approximately half the compounds were polymorphic, often havingone to three forms. About one-third of the compounds formed hydrates,and about one-third formed solvates. Data from coerystal screens of 64compounds showed that 60% formed coerystals other than hydrates orsolvates. (G. P. Stahly, Crystal Growth & Design (2007), 7(6),1007-1026.)

Combination Therapy

A compound of the invention can be administered as the sole activepharmaceutical agent (i.e., mono-therapy), or it can be used incombination with one or more pharmaceutical agents (i.e.,combination-therapy), such as pharmaceutical agents, such as, knownanti-diabetic agents, either administered together or separately for thetreatment of the diseases, conditions, and disorders described herein.Therefore, another aspect of the present invention includes methods oftreatment of a metabolic related disorder, including a weight-relateddisorder, such as obesity, comprising administering to an individual inneed thereof a Compound of Formula (Ia) or a pharmaceutically acceptablesalt, solvate, or hydrate thereof, in combination with one or morepharmaceutical agents, such as anti-diabetic agents, as describedherein.

In accordance with the present invention, the combination can be used bymixing the respective active components, a Compound of Formula (Ia) anda pharmaceutical agent, either together or independently optionally witha physiologically acceptable carrier, excipient, binder, diluent, etc.,as described herein, and administering the mixture or mixtures eitherorally or non-orally as a pharmaceutical composition(s). When a Compoundof Formula (Ia) is administered as a combination therapy with anotheractive compound the Compound of Formula (Ta) and the pharmaceuticalagent can be formulated as separate pharmaceutical compositions given atthe same time or at different times; or the Compound of Formula (Ia) andthe pharmaceutical agent can be formulated together as a single unitdosage.

Suitable pharmaceutical agents that can be used in combination with thecompounds of the present invention include anti-obesity agents such asapolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors; MCR-4 agonists, cholecystokinin-A (CCK-A)agonists; serotonin and norepinephrine reuptake inhibitors (for example,sibutramine); sympathomimetic agents; β3 adrenergic receptor agonists;dopamine agonists (for example, bromocriptine); melanocyte-stimulatinghormone receptor analogues; cannabinoid 1 receptor antagonists [forexample, SR141716:N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide];melanin concentrating hormone antagonists; leptin (the OB protein);leptin analogues; leptin receptor agonists; galanin antagonists; lipaseinhibitors (such as tetrahydrolipstatin, i.e., orlistat); anorecticagents (such as a bombesin agonist); neuropeptide-Y antagonists;thyromimetic agents; dehydroepiandrosterone or an analogue thereof;glucocorticoid receptor agonists or antagonists; orexin receptorantagonists; urocortin binding protein antagonists; glucagon-likepeptide-1 (GLP-1) receptor agonists; ciliary neurotrophic factors (suchas Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown,N.Y. and Procter & Gamble Company, Cincinnati, Ohio); humanagouti-related proteins (AGRP); ghrelin receptor antagonists; histamine3 receptor (H3R) antagonists or inverse agonists; neuromedin U receptoragonists; noradrenergic anorectic agents (for example, phentermine,mazindol and the like); appetite suppressants (for example, bupropion);and 5-HT₂, agonists (for example, Iorcaserin).

Other anti-obesity agents, including the agents set forth infra, arewell known, or will be readily apparent in light of the instantdisclosure, to one of ordinary skill in the art. In some embodiments,the anti-obesity agents are selected from the group consisting oforlistat, sibutramine, bromocriptine, ephedrine, leptin,pseudoephedrine, and Iorcaserin. In a further embodiment, compounds ofthe present invention and combination therapies are administered inconjunction with exercise and/or a calorie-controlled diet.

It is understood that the scope of combination-therapy of the compoundsof the present invention with anti-obesity agents, anorectic agents,appetite suppressant and related agents is not limited to those listedabove, but includes in principle any combination with any pharmaceuticalagent or pharmaceutical composition useful for the treatment ofoverweight and obese individuals.

It is understood that the scope of combination-therapy of the compoundsof the present invention with other pharmaceutical agents is not limitedto those listed herein, supra or infra, but includes in principle anycombination with any pharmaceutical agent or pharmaceutical compositionuseful for the treatment of diseases, conditions or disorders that arelinked to metabolic related disorders.

Some embodiments of the present invention include methods of treatmentof a disease, disorder, condition or complication thereof as describedherein, comprising administering to an individual in need of suchtreatment a therapeutically effective amount or dose of a Compound ofFormula (Ia) in combination with at least one pharmaceutical agentselected from the group consisting of: sulfonylureas (for example,tolbutamide (Orinase); acetohexamide (Dymelor); tolazamide (Tolinase);chlorpropamide (Diabinese); glipizide (Glucotrol); glyburide (Diabeta,Micronase, Glynase); glimepiride (Amaryl); gliclazide (Diamicron); andsulfonylureas known in the art); meglitinides (for example, repaglinide(Prandin), nateglinide (Starlix), mitiglinide, and other meglitinidesknown in the art); biguanides (for example, phenformin, metformin,buformin, and biguanides known in the art); α-glucosidase inhibitors(for example, acarbose, miglitol, and alpha-glucosidase inhibitors knownin the art); thiazolidinediones-peroxisome proliferators-activatedreceptor-γ (i.e., PPAR-γ) agonists (for example, rosiglitazone(Avandia), pioglitazone (Actos), troglitazone (Rezulin), rivoglitazone,ciglitazone, and thiazolidinediones known in the art); insulin andinsulin analogues; anti-diabetic peptide analogues (for example,exenatide, liraglutide, taspoglutide, and anti-diabetic peptidesanalogues know in the art); HMG-CoA reductase inhibitors (for example,rosuvastatin, pravastatin and its sodium salt, simvastatin, lovastatin,atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin,pravastatin, and other HMG-CoA reductase inhibitors known in the art);cholesterol-lowering drugs (for example, fibrates that include:bezafibrate, beclobrate, binifibrate, ciplofibrate, clinofibrate,clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil,nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate, andother fibrates known in the art; bile acid sequestrants which include:cholestyramine, colestipol and the like; and niacin); antiplateletagents (for example, aspirin and adenosine diphosphate receptorantagonists that include: clopidogrel, ticlopidine and the like);angiotensin-converting enzyme inhibitors (for example, captopril,enalapril, alacepril, delapril; ramipril, lisinopril, imidapril,benazepril, ceronapril, cilazapril, enalaprilat, fosinopril,moveltopril, perindopril, quinapril, spirapril, temocapril,trandolapril, and other angiotensin converting enzyme inhibitors knownin the art); angiotensin II receptor antagonists [for example, losartan(and the potassium salt form), and other angiotensin II receptorantagonists known in the art; adiponectin; squalene synthesis inhibitors{for example, (S)-α-[bis[2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonic acid, mono potassium salt(BMS-188494) and other squalene synthesis inhibitors known in the art};and the like. In some embodiments, compounds of the present inventionand the pharmaceutical agents are administered separately. In furtherembodiments, compounds of the present invention and the pharmaceuticalagents are administered simultaneously.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include, but are not limited to:amylin agonists (for example, pramlintide); insulin secretagogues (forexample, GLP-1 agonists, exendin-4, and insulinotropin (NN2211)); acylCoA cholesterol acetyltransferase inhibitors (for example, ezetimibe,eflucimibe, and other acyl CoA cholesterol acetyltransferase inhibitorsknown in the art); cholesterol absorption inhibitors (for example,ezetimibe, pamaqueside and other cholesterol absorption inhibitors knownin the art); cholesterol ester transfer protein inhibitors (for example,CP-529414, JTT-705, CETi-1, and other cholesterol ester transfer proteininhibitors known in the art); microsomal triglyceride transfer proteininhibitors (for example, implitapide, and other microsomal triglyceridetransfer protein inhibitors known in the art); cholesterol modulators(for example, NO-1886, and other cholesterol modulators known in theart); bile acid modulators (for example, GT103-279 and other bile acidmodulators known in the art); insulin signaling pathway modulators;inhibitors of protein tyrosine phosphatases (PTPases); non-smallmolecule mimetics and inhibitors of glutamine-fructose-6-phosphateamidotransferase (GFAT); compounds influencing a dysregulated hepaticglucose production; inhibitors of glucose-6-phosphatase (G6Pase);inhibitors of fructose-1,6-bisphosphatase (F-1,6-BPase); inhibitors ofglycogen phosphorylase (GP); glucagon receptor antagonists; inhibitorsof phosphoenolpyruvate carboxykinase (PEPCK); pyruvate dehydrogenasekinase (PDHK) inhibitors; insulin sensitivity enhancers; insulinsecretion enhancers; inhibitors of gastric emptying; α₂-adrenergicantagonists; retinoid X receptor (RXR) agonists; and dipeptidylpeptidase-4 (DPP-IV) inhibitors; and the like.

Tripartite Combinations

Some aspects of the present invention include compounds of Formula (Ia)that can be employed in any of the methods, pharmaceutical products,uses, compounds, and pharmaceutical agents, as described herein, incombination with two distinct pharmaceutical agents.

In some embodiments, the two distinct pharmaceutical agents are selectedfrom any of the pharmaceutical agents, or classes of pharmaceuticalagents described herein. In some embodiments, the two distinctpharmaceutical agents are selected from: a DPP-IV inhibitor, abiguanide, an alpha-glucosidase inhibitor, an insulin analogue, asulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione,and an anti-diabetic peptide analogue. In some embodiments, the twodistinct pharmaceutical agents include every combination selected frompharmaceutical agents of the following group: a DPP-IV inhibitor, abiguanide, an alpha-glucosidase inhibitor, a sulfonylurea, and an SGLT2inhibitor.

Some embodiments of the present invention include every combination ofone or more compounds selected from compounds of the following group andpharmaceutically acceptable salts, solvates, and hydrates thereof: aDPP-IV inhibitor selected from:3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile;(1S,3S,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile;2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile;8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine;1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid;4(S)-fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile;1-[(2S,3S,11bS)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one;(2S,4S)-2-cyano-4-fluoro-1-[(2-hydroxy-1,1-dimethyl)ethylamino]acetylpyrrolidine;8-(cis-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-3-methyl-7-(3-methyl-but-2-enyl)-1-(2-oxo-2-phenylethyl)-3,7-dihydro-purine-2,6-dione;1-((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5difluoropiperidin-2-one;(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile;5-{(S)-2-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylicacid bis-dimethylamide;((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone;(2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile;6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione;2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile;(2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile;(2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile;(3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone;(2S,4S)-1-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile;and(1S,6R)-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohex-3-en-1-amine;a biguanide selected from: phenformin ((phenylethyl)biguanide);metformin (dimethylbiguanide); buformin (butylbiguanide); and proguanil(1-(p-chlorophenyl)-5-isopropylbiguanide); an alpha-glucosidaseinhibitor selected from: acarbose((2R,3R,4R,5R)-4-((2R,3R,4R,5S,6R)-5-((2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-((1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-2-yloxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal);miglitol((2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol);and voglibose((1S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetraol);an insulin analogue selected from: NPH insulin (also known as Humulin N,Novolin N, NPH letin II, and insulin isophane); insulin lispro(28B-L-lysine-29B-L-proline-insulin, wherein insulin is human insulin);insulin aspart (28B-L-aspartic acid-insulin, wherein insulin is humaninsulin); and insulin glulisine (3B-1-lysine-29B-1-glutamicacid-insulin, wherein insulin is human insulin); a sulfonylurea selectedfrom: tolbutamide (Orinase,N-(butylcarbamoyl)-4-methylbenzenesulfonamide); acetohexamide (Dymelor,4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide); tolazamide(Tolinase, N-(azepan-1-ylcarbamoyl)-4-methylbenzenesulfonamide);chlorpropamide (Diabinese,4-chloro-N-(propylcarbamoyl)benzenesulfonamide); glipizide (Glucotrol,N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide);glibenclamide, also known as glyburide (Diabeta, Micronase, Glynase,5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide);glimepiride (Amaryl,3-ethyl-4-methyl-N-(4-(N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide);and gliclazide (Diamicron,N-(hexahydrocyclopenta[c]pyrrol-2(1H)-ylcarbamoyl)-4-methylbenzenesulfonamide);an SGLT2 inhibitor selected from: dapagliflozin((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol);remogliflozin (ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1H-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methylcarbonate); ASP1941, canagliflozin((2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol);ISIS 388626; sergliflozin (ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-(4-methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methylcarbonate), AVE2268((2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3-yloxy)tetrahydro-2H-pyran-3,4,5-triol),BT10773, CSG453; and LX4211; a meglitinide selected from: repaglinide(Prandin,(S)-2-ethoxy-4-(2-(3-methyl-1-(2-(piperidin-1-yl)phenyl)butylamino)-2-oxoethyl)benzoicacid); nateglinide (Starlix,(R)-2-((1r,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropanoicacid); and mitiglinide((S)-2-benzyl-4-((3aR,7aS)-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoicacid); a thiazolidinedione selected from: rosiglitazone (Avandia,5-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione);pioglitazone (Actos,5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione);troglitazone (Rezulin,5-(4-((6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy)benzyl)thiazolidine-2,4-dione);rivoglitazone(5-(4-((6-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4-dione);and ciglitazone(5-(4-((1-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione); andan anti-diabetic peptide analogue selected from: exenatide; liraglutide;and taspoglutide.

In some embodiments, the two distinct pharmaceutical agents includeevery combination selected from pharmaceutical agents of the followinggroup: sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin,phenformin, metformin, buformin, acarbose, miglitol, voglibose,tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide,glibenclamide, glimepiride, gliclazide, dapagliflozin, remogliflozin,and sergliflozin.

Dipeptidyl Peptidase IV Inhibitors

Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) exhibits catalyticactivity against a broad range of peptide substrates that includespeptide hormones, neuropeptides, and chemokines. The incretinsglucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropicpolypeptide (GIP), which stimulate glucose-dependent insulin secretionand otherwise promote blood glucose homeostasis, are rapidly cleaved byDPP-IV at the position-2 alanine leading to inactivation of theirbiological activity. Peptide YY (PYY) is a gut peptide that has beenimplicated in modulating satiety (Chaudhri et al., Annu Rev Physiol(2008) 70:239-255). PYY is released into the circulation as PYY₁₋₃₆ andPYY₃₋₃₆ (Eberlein et al., Peptides (1989) 10:797-803). PYY₃₋₃₆ isgenerated from PYY₁₋₃₆ by cleavage of the N-terminal Tyr and Proresidues by DPP-IV. Both pharmacological and genetic attenuation ofDPP-IV activity is associated with enhanced incretin action, increasedinsulin, and lower blood glucose in vivo. Genetic attenuation of DPP-IVactivity has been shown to provide resistance to obesity and to improveinsulin sensitivity. DPP-IV inhibitors have shown to be useful astherapeutics, for example, oral administration of vildagliptin(1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile)or sitagliptin(3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one)to human patients suffering with type 2 diabetes has been found toreduce fasting glucose and postprandial glucose excursion in associationwith significantly reduced HbA_(1c) levels. For reviews on theapplication of DPP-IV inhibitors for the treatment of type 2 diabetes,reference is made to the following publications: (1) H.-U. Demuth, etal., “Type 2 diabetes-therapy with DPP-IV inhibitors,” Biochim. Biophys.Acta, 1751: 33-44 (2005), and (2) K. Augustyns, et al., “Inhibitors ofproline-specific dipeptidyl peptidases: DPP-IV inhibitors as a novelapproach for the treatment of type 2 diabetes”, Expert Opin. Ther.Patents, 15: 1387-1407 (2005).

Accordingly, suitable pharmaceutical agents include DPP-IV inhibitorsthat can be used in conjunction with compounds of the present inventioneither dosed separately or together. DPP-IV inhibitors are well-known inthe art or can be readily identified and their in vitro biologicalactivity determined using any number of methods available, for example,O'Brien, M., Daily, B., Schurria, M., “Assay for DPPIV activity using ahomogeneous, luminescent method,” Cell Notes, Issue 11, 2005; see alsothe DPPIV-Glo™ Protease Assay Technical Bulletin #TB339.

Examples of DPP-IV inhibitors are described in Villhauer et al., J. Med.Chem. (2003) 46:2774-2789, for LAF237; Ahren et al., J. Clin.Endocrinol. Metab. (2004) 89:2078-2084; Villhauer et al., J. Med. Chem.(2002) 45:2362-2365 for NVP-DPP728; Ahren et al., Diabetes Care (2002)25:869-875 for NVP-DPP728; Peters et al., Bioorg. Med. Chem. Lett.(2004) 14:1491-1493; Caldwell et al., Bioorg. Med. Chem. Lett. (2004)14:1265-1268; Edmondson et al., Bioorg. Med. Chem. Lett. (2004)14:5151-5155; and Abe et al., J. Na.t Prod. (2004) 67:999-1004.

Specific examples of DPP-IV inhibitors include, but are not limited to,dipeptide derivatives or dipeptide mimetics such as alanine-pyrrolidide,isoleucine-thiazolidide, and the pseudosubstrate N-valyl prolyl,O-benzoyl hydroxylamine, as described, for example, in U.S. Pat. No.6,303,661.

Some embodiments of the present invention include every combination ofone or more DPP-IV inhibitors selected from the DPP-IV inhibitors foundin U.S. Pat. Nos. 6,869,947, 6,867,205, 6,861,440, 6,849,622, 6,812,350,6,803,357, 6,800,650, 6,727,261, 6,716,843, 6,710,040, 6,706,742,6,645,995, 6,617,340, 6,699,871, 6,573,287, 6,432,969, 6,395,767,6,380,398, 6,303,661, 6,242,422, 6,166,063, 6,100,234, and 6,040,145.

Some embodiments of the present invention include every combination ofone or more DPP-IV inhibitors selected from the DPP-IV inhibitors foundin U.S. Pat. Nos. 2005059724, 2005059716, 2005043292, 2005038020,2005032804, 2005004205, 2004259903, 2004259902, 2004259883, 2004254226,2004242898, 2004229926, 2004180925, 2004176406, 2004138214, 2004116328,2004110817, 2004106656, 2004097510, 2004087587, 2004082570, 2004077645,2004072892, 2004063935, 2004034014, 2003232788, 2003225102, 2003216450,2003216382, 2003199528, 2003195188, 2003162820, 2003149071, 2003134802,2003130281, 2003130199, 2003125304, 2003119750, 2003119738, 2003105077,2003100563, 2003087950, 2003078247, 2002198205, 2002183367, 2002103384,2002049164, and 2002006899.

Some embodiments of the present invention include every combination ofone or more DPP-IV inhibitors selected from the DPP-IV inhibitors foundin International Patent Application Publication Nos. WO 2005/087235, WO2005/082348, WO 2005/082849, WO 2005/079795, WO 2005/075426, WO2005/072530, WO 2005/063750, WO 2005/058849, WO 2005/049022, WO2005/047297, WO 2005/044195, WO 2005/042488, WO 2005/040095, WO2005/037828, WO 2005/037779, WO 2005/034940, WO 2005/033099, WO2005/032590, WO 2005/030751, WO 2005/030127, WO 2005/026148, WO2005/025554, WO 2005/023762, WO 2005/020920, WO 05/19168, WO 05/12312,WO 05/12308, WO 05/12249, WO 05/11581, WO 05/09956, WO 05/03135, WO05/00848, WO 05/00846, WO 04/112701, WO 04/111051, WO 04/111041, WO04/110436, WO 04/110375, WO 04/108730, WO 04/104216, WO 04/104215, WO04/103993, WO 04/103276, WO 04/99134, WO 04/96806, WO 04/92128, WO04/87650, WO 04/87053, WO 04/85661, WO 04/85378, WO 04/76434, WO04/76433, WO 04/71454, WO 04/69162, WO 04/67509, WO 04/64778, WO04/58266, WO 04/52362, WO 04/52850, WO 04/50022, WO 04/50658, WO04/48379, WO 04/46106, WO 04/43940, WO 04/41820, WO 04/41795, WO04/37169, WO 04/37181, WO 04/33455, WO 04/32836, WO 04/20407, WO04/18469, WO 04/18468, WO 04/18467, WO 04/14860, WO 04/09544, WO04/07468, WO 04/07446, WO 04/04661, WO 04/00327, WO 03/106456, WO03/104229, WO 03/101958, WO 03/101448, WO 03/99279, WO 03/95425, WO03/84940, WO 03/82817, WO 03/80633, WO 03/74500, WO 03/72556, WO03/72528, WO 03/68757, WO 03/68748, WO 03/57666, WO 03/57144, WO03/55881, WO 03/45228, WO 03/40174, WO 03/38123, WO 03/37327, WO03/35067, WO 03/35057, WO 03/24965, WO 03/24942, WO 03/22871, WO03/15775, WO 03/04498, WO 03/04496, WO 03/02530, WO 03/02596, WO03/02595, WO 03/02593, WO 03/02553, WO 03/02531, WO 03/00181, WO03/00180, WO 03/00250, WO 02/83109, WO 02/83128, WO 02/76450, WO02/68420, WO 02/62764, WO 02/55088, WO 02/51836, WO 02/38541, WO02/34900, WO 02/30891, WO 02/30890, WO 02/14271, WO 02/02560, WO01/97808, WO 01/96295, WO 01/81337, WO 01/81304, WO 01/68603, WO01/55105, WO 01/52825, WO 01/34594, WO 00/71135, WO 00/69868, WO00/56297, WO 00/56296, WO 00/34241, WO 00/23421, WO 00/10549, WO99/67278, WO 99/62914, WO 99/61431, WO 99/56753, WO 99/25719, WO99/16864, WO 98/50066, WO 98/50046, WO 98/19998, WO 98/18763, WO97/40832, WO 95/29691, WO 95/15309, WO 93/10127, WO 93/08259, and WO91/16339.

Some embodiments of the present invention include every combination ofone or more DPP-IV inhibitors selected from the DPP-IV inhibitors foundin Patent Publication Nos. EP 1517907, EP 1513808, EP 1492777, EP1490335, EP 1489088, EP 1480961, EP 1476435, EP 1476429, EP 1469873, EP1465891, EP 1463727, EP 1461337, EP 1450794, EP 1446116, EP 1442049, EP1441719, EP 1426366, EP 1412357, EP1406873, EP 1406872, EP 1406622, EP1404675, EP 1399420, EP 1399471, EP 1399470, EP 1399469, EP 1399433, EP1399154, EP 1385508, EP 1377288, EP 1355886, EP 1354882, EP 1338592, EP1333025, EP 1304327, EP 1301187, EP 1296974, EP 1280797, EP 1282600, EP1261586, EP 1258476, EP 1254113, EP 1248604, EP 1245568, EP 1215207, EP1228061, EP 1137635, EP 1123272, EP 1104293, EP 1082314, EP 1050540, EP1043328, EP 0995440, EP 0980249, EP 0975359, EP 0731789, EP 0641347, EP0610317, EP 0528858, CA 2466870, CA 2433090, CA 2339537, CA 2289125, CA2289124, CA 2123128, DD 296075, DE 19834591, DE 19828113, DE 19823831,DE 19616486, DE 10333935, DE 10327439, DE 10256264, DE 10251927, DE10238477, DE 10238470, DE 10238243, DE 10143840, FR 2824825, FR 2822826,JP2005507261, JP 2005505531, JP 2005502624, JP 2005500321, JP2005500308, JP2005023038, JP 2004536115, JP 2004535445, JP 2004535433,JP 2004534836, JP 2004534815, JP 2004532220, JP 2004530729, JP2004525929, JP 2004525179, JP 2004522786, JP 2004521149, JP 2004503531,JP 2004315496, JP 2004244412, JP 2004043429, JP 2004035574, JP2004026820, JP 2004026678, JP 2004002368, JP 2004002367, JP 2003535898,JP 2003535034, JP 2003531204, JP2003531191, JP 2003531118, JP2003524591, JP2003520849, JP 2003327532, JP 2003300977, JP 2003238566,JP 2002531547, JP 2002527504, JP 2002517401, JP 2002516318, JP2002363157, JP 2002356472, JP 2002356471, JP 2002265439, JP 2001510442,JP 2000511559, JP 2000327689, JP 2000191616, JP 1998182613, JP1998081666, JP 1997509921, JP 1995501078, and JP 1993508624.

In some embodiments, the DPP-IV inhibitor has an IC₅₀ of less than about10 μM, less than about 1 μM, less than about 100 nM, less than about 75nM, less than about 50 nM, less than about 25 nM, less than about 20 nM,less than about 15 nM, less than about 10 nM, less than about 5 nM, lessthan about 4 nM, less than about 3 nM, less than about 2 nM, or lessthan about 1 nM, in any one of the DPP-IV inhibitor assays known in theart, including the assays in the references disclosed herein. In someembodiments, the DPP-IV inhibitor has an IC₅₀ of less than about 50 nM,less than about 25 nM, less than about 20 nM, less than about 15 nM,less than about 10 nM, less than about 5 nM, less than about 4 nM, lessthan about 3 nM, less than about 2 nM, or less than about 1 nM, in anyone of the DPP-IV inhibitor assays known in the art, including theassays in the references disclosed herein.

In some embodiments, the DPP-IV inhibitor is a selective DPP-IVinhibitor, wherein the selective DPP-IV inhibitor has a selectivity forhuman plasma DPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 ofat least about 10-fold. In some embodiments, the DPP-IV inhibitor is aselective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has aselectivity for human plasma DPP-IV over one or more of PPCE, DPP-II,DPP-8 and DPP-9 of at least about 100-fold. In some embodiments, theDPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selectiveDPP-IV inhibitor has a selectivity for human plasma DPP-IV over one ormore of PPCE, DPP-JI, DPP-8 and DPP-9 of at least about 10-fold. In someembodiments, the DPP-IV inhibitor is a selective DPP-IV inhibitor,wherein the selective DPP-IV inhibitor has a selectivity for humanplasma DPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of atleast about 1000-fold.

In some embodiments, the DPP-IV inhibitor is orally active.

In some embodiments, the DPP-IV inhibitor is an inhibitor of humanDPP-IV.

Some embodiments of the present invention include every combination ofone or more DPP-IV inhibitors selected from DPP-IV inhibitors of thefollowing group and pharmaceutically acceptable salts, solvates, andhydrates thereof:3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile;(1S,3S,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile;2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile;8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine;1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid;4(S)-fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile;1-[(2S,3S,11bS)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one;(2S,4S)-2-cyano-4-fluoro-1-[(2-hydroxy-1,1-dimethyl)ethylamino]acetylpyrrolidine;8-(cis-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-3-methyl-7-(3-methyl-but-2-enyl)-1-(2-oxo-2-phenylethyl)-3,7-dihydro-purine-2,6-dione;1-((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5difluoropiperidin-2-one;(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile;5-{(S)-2-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylicacid bis-dimethylamide;((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone;(2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile;6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione;2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile;(2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile;(2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile;(3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone;(2S,4S)-1-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile;and(1S,6R)-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohex-3-en-1-amine.

Sitagliptin phosphate (Januvia®, MK-0431, dihydrogenphosphate salt of3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one)is marketed by Merck & Co. for once-daily oral treatment of type 2diabetes. Januvia was first launched in Mexico followed bycommercialization in the U.S. In 2007, the product was approved by theEuropean Medicines Evaluation Agency (EMEA) and is currently availablein the U.K., Germany and Spain. In 2009, Januvia was approved andlaunched in Japan. In addition, Merck has also filed for approval ofJanuvia in the U.S. as an adjunct to diet and exercise and incombination with other therapies to improve glycemic control in thetreatment of diabetes. The compound,3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one,and pharmaceutically acceptable salts thereof are disclosed ininternational patent publication WO2003/004498. Some embodiments of thepresent invention include every combination of one or more compoundsselected from compounds disclosed in WO2003/004498 and pharmaceuticallyacceptable salts, solvates, and hydrates thereof. In some embodiments,the DPP-IV inhibitor is selected from3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

In some embodiments, the DPP-IV inhibitor is3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-onephosphate:

The crystalline form of3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-onephosphate salt monohydrate is disclosed in international patentpublication WO2005/003135. In some embodiments, the DPP-IV inhibitor iscrystalline3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-onephosphate monohydrate.

Vildagliptin (Galvus®, LAF-237,1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile)is another DPP-IV inhibitor and was first commercialized in Brazil andMexico by Novartis for oral, once-daily treatment of type 2 diabetes. In2008, a marketing authorization application (MAA) was approved in theE.U. for this indication and launch took place in the U.K. in March,2008. An approvable letter has been received for the regulatoryapplication filed in the U.S. Vildagliptin was approved in Japan in2010. The compound,1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile,is disclosed in international patent publication WO2000/034241. Someembodiments of the present invention include every combination of one ormore compounds selected from compounds disclosed in WO2000/034241 andpharmaceutically acceptable salts, solvates, and hydrates thereof. Insome embodiments, the DPP-IV inhibitor is selected from1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Certain salts of the compound,1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile,are disclosed in international patent publication WO2007/019255. In someembodiments, the DPP-IV inhibitor is1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrileHCl:

Saxagliptin (Onglyza™, BMS-477118,(1S,3S,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile)is another DPP-IV inhibitor, which was launched in 2009 by AstraZenecaand Bristol-Myers Squibb in the U.S. for the treatment of type 2diabetes. In 2009, the product was approved in the E.U. for thetreatment of type 2 diabetes independently or in combination withmetformin. Phase 3 clinical studies are ongoing in Japan for thetreatment of type 2 diabetes. The compound,(1S,3S,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile,is disclosed in international patent publication WO2001/068603. Someembodiments of the present invention include every combination of one ormore compounds selected from compounds disclosed in WO2001/068603 andpharmaceutically acceptable salts, solvates, and hydrates thereof. Insome embodiments, the DPP-IV inhibitor is selected from(1S,3S,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Takeda has filed for regulatory approval of the DPP-IV inhibitor,alogliptin (SYR-322, Nesina®,2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile)in Japan and the U.S for the once-daily, oral treatment of type 2diabetes. The compound,2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile,and pharmaceutically acceptable salts thereof are disclosed ininternational patent publication WO 2005/095381. Some embodiments of thepresent invention include every combination of one or more compoundsselected from compounds disclosed in WO 2005/095381 and pharmaceuticallyacceptable salts, solvates, and hydrates thereof. In some embodiments,the DPP-IV inhibitor is selected from2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

The crystalline form of2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrileis disclosed in international patent publication WO2007/035372. In someembodiments, the DPP-IV inhibitor is2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrilebenzoate:

Linagliptin (BI-1356, Ondero®, Tradjenta™,8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine)is a DPP-IV inhibitor in phase 3 clinical development at BoehringerIngelheim to evaluate its potential as add-on therapy to metformin forthe treatment of type 2 diabetes. The compound,8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine,is disclosed in international patent publication WO2004/018468. Someembodiments of the present invention include every combination of one ormore compounds selected from compounds disclosed in WO2004/018468 andpharmaceutically acceptable salts, solvates, and hydrates thereof. Insome embodiments, the DPP-IV inhibitor is selected from8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Certain polymorphs of the compound,8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine,are disclosed in international patent publication WO 2007/128721. Insome embodiments, the DPP-IV inhibitor is a crystalline form of8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine.

Dutogliptin (PHX-1149, 1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-ylboronic acid) is a DPP-IV inhibitor in phase 3 clinical trials byPhenomix and Forest for the oral, once-daily treatment of type 2diabetes. The compound, 1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid, and pharmaceutically acceptable saltsthereof are disclosed in international patent publication WO2005/047297.Some embodiments of the present invention include every combination ofone or more compounds selected from compounds disclosed in WO2005/047297and pharmaceutically acceptable salts, solvates, and hydrates thereof.In some embodiments, the DPP-IV inhibitor is selected from1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid, andpharmaceutically acceptable salts, solvates, and hydrates thereof:

The crystalline form of1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid tartrateis disclosed in international patent publication WO2008/027273. In someembodiments, the DPP-IV inhibitor is1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid tartrate:

Melogliptin (GRC-8200,4(S)-fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile)is a DPP-IV inhibitor currently undergoing phase 2 clinical trials byGlenmark Pharmaceuticals and Merck KGaA for the treatment of type 2diabetes. The compound,4(S)-fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile,is disclosed in international patent publication WO2006/040625. Someembodiments of the present invention include every combination of one ormore compounds selected from compounds disclosed in WO2006/040625 andpharmaceutically acceptable salts, solvates, and hydrates thereof. Insome embodiments, the DPP-IV inhibitor is selected from4(S)-fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Carmegliptin (R-1579,1-[(2S,3S,11bS)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one)is a DPP-IV inhibitor. The compound,1-[(2S,3S,11bS)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one,is disclosed in international patent publication WO2005/000848. Someembodiments of the present invention include every combination of one ormore compounds selected from compounds disclosed in WO2005/000848 andpharmaceutically acceptable salts, solvates, and hydrates thereof. Insome embodiments, the DPP-IV inhibitor is selected from1-[(2S,3S,11bS)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Taisho disclosed (2S,4S)-2-cyano-4-fluoro-1-[(2-hydroxy-1,1-dimethyl)ethylamino]acetylpyrrolidine, a DPP-IV inhibitor in US patentpublication US 2007/0112059. Some embodiments of the present inventioninclude every combination of one or more compounds selected fromcompounds disclosed in US 2007/0112059 and pharmaceutically acceptablesalts, solvates, and hydrates thereof. In some embodiments, the DPP-IVinhibitor is selected from(2S,4S)-2-cyano-4-fluoro-1-[(2-hydroxy-1,1-dimethyl)ethylamino]acetylpyrrolidine,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Sanofi-Aventis disclosed a series of substituted bicyclic8-pyrrolidineoxanthine derivatives as DPP-IV inhibitors in USpublication US 2007/0167468. Some embodiments of the present inventioninclude every combination of one or more compounds selected fromcompounds disclosed in US publication US 2007/0167468 andpharmaceutically acceptable salts, solvates, and hydrates thereof. Insome embodiments, the DPP-IV inhibitor is selected from8-(cis-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-3-methyl-7-(3-methyl-but-2-enyl)-1-(2-oxo-2-phenylethyl)-3,7-dihydro-purine-2,6-dione,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Pfizer disclosed a series of 3-amino-pyrrolidine-4-lactam derivatives asDPP-IV inhibitors in international patent publication WO2007/148185.Some embodiments of the present invention include every combination ofone or more compounds selected from compounds disclosed in WO2007/148185and pharmaceutically acceptable salts, solvates, and hydrates thereof.One such compound is1-((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5difluoropiperidin-2-one.In some embodiments, the DPP-IV inhibitor is selected from1-((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5difluoropiperidin-2-one,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Syrrx disclosed a series of substituted pyrimidine-2,4(1H,3H)-dionederivatives as DPP-IV inhibitors in international patent publicationWO2005/095381. Some embodiments of the present invention include everycombination of one or more compounds selected from compounds disclosedin WO2005/095381 and pharmaceutically acceptable salts, solvates, andhydrates thereof. One such compound is(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile.In some embodiments, the DPP-IV inhibitor is selected from(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Various crystalline forms of(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrilesuccinic acid salt are disclosed in international patent publicationWO2008/067465. One embodiment of the present invention pertains to anyone or more crystalline forms of(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrilesuccinic acid salt as described in international patent publicationWO2008/067465. In some embodiments, the DPP-IV inhibitor is crystalline(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrilesuccinic acid salt:

Alantos disclosed a series of substituted 2-cyano-pyrrolidinederivatives as DPP-IV inhibitors in international patent publicationWO2006/116157. Some embodiments of the present invention include everycombination of one or more compounds selected from compounds disclosedin WO2006/116157 and pharmaceutically acceptable salts, solvates, andhydrates thereof. One such compound is5-{(S)-2-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylicacid bis-dimethylamide. In some embodiments, the DPP-IV inhibitor isselected from5-{(S)-2-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylicacid bis-dimethylamide, and pharmaceutically acceptable salts, solvates,and hydrates thereof:

Mitsubishi disclosed a series of 2,4-disubstituted pyrrolidinederivatives as DPP-IV inhibitors in international patent publicationWO2002/0014271. Some embodiments of the present invention include everycombination of one or more compounds selected from compounds disclosedin WO2002/0014271 and pharmaceutically acceptable salts, solvates, andhydrates thereof. One such compound is((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone.In some embodiments, the DPP-IV inhibitor is selected from((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Various crystalline forms of((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanonesalts are disclosed in international patent publication WO2006/088129and US publication 2009/0216016. One embodiment of the present inventionpertains to any one or more crystalline forms of((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanonesalt as described in international patent publication WO2006/088129 andUS publication 2009/0216016. In some embodiments, the DPP-IV inhibitoris crystalline((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone2.5 hydrobromide salt:

or a mono or a dihydrate thereof. In some embodiments, the DPP-IVinhibitor is crystalline((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanonedi-hydrobromide salt.

Kyorin disclosed a series of pyrrolidinecarbonitrile derivatives asDPP-IV inhibitors in international patent publication WO2008/114857 andUS publication US 2008/0146818. Some embodiments of the presentinvention include every combination of one or more compounds selectedfrom compounds disclosed in WO2008/114857 and US publication US2008/0146818, and pharmaceutically acceptable salts, solvates, andhydrates thereof. One such compound is(2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile.In some embodiments, the DPP-IV inhibitor is selected from(2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Dainippon Sumitomo disclosed a series of bicyclic pyrrole derivatives asDPP-IV inhibitors in international patent publication WO2006/068163 andUS publication US 2009/0192129. Some embodiments of the presentinvention include every combination of one or more compounds selectedfrom compounds disclosed in WO2006/068163 and US publication US2009/0192129 and pharmaceutically acceptable salts, solvates, andhydrates thereof. One such compound is(6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione.In some embodiments, the DPP-IV inhibitor is selected from(6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Dainippon Sumitomo disclosed2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrileas a DPP-IV inhibitor in international patent publication WO2009/084497.In some embodiments, the DPP-IV inhibitor is selected from2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Hoffmann-La Roche disclosed a series of N-substituted pyrrolidinederivatives as DPP-IV inhibitors in international patent publication WO03/037327. Some embodiments of the present invention include everycombination of one or more compounds selected from compounds disclosedin WO 03/037327 and pharmaceutically acceptable salts, solvates, andhydrates thereof. One such compound is(2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile.In some embodiments, the DPP-IV inhibitor is selected from(2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Various crystalline forms of(2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrilemethanesulfonic acid salt are disclosed in international patentpublication WO2006/100181. In some embodiments, the DPP-IV inhibitor is(2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrilemethanesulfonic acid salt (i.e., mesylate):

Other compounds disclosed by Hoffmann-La Roche in international patentpublication WO 03/037327 include(2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,and pharmaceutically acceptable salts thereof, such as themethanesulfonic acid salt. In some embodiments, the DPP-IV inhibitor isselected from(2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

In some embodiments, the DPP-IV inhibitor is(2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrilemethanesulfonic acid:

Various crystalline forms of(2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrilefumaric acid salt are disclosed in international patent publicationWO2007/071576. In some embodiments, the DPP-IV inhibitor is(2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrilefumaric acid salt (i.e., fumarate):

Pfizer disclosed a series of proline derivatives as DPP-IV inhibitors ininternational patent publication WO2005/116014. Some embodiments of thepresent invention include every combination of one or more compoundsselected from compounds disclosed in WO2005/116014 and pharmaceuticallyacceptable salts, solvates, and hydrates thereof. One such compound is(3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone.In some embodiments, the DPP-IV inhibitor is selected from(3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

GlaxoSmithKline disclosed a series of fluoropyrrolidine derivatives asDPP-IV inhibitors in international patent publication WO 03/002531. Someembodiments of the present invention include every combination of one ormore compounds selected from the DPP-IV inhibitors disclosed in WO03/037327 and pharmaceutically acceptable salts, solvates, and hydratesthereof. One such compound is(2S,4S)-1-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile(Denagliptin). In some embodiments, the DPP-IV inhibitor is selectedfrom(2S,4S)-1-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Various crystalline forms of(2S,4S)-1-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrileand salts have been disclosed in international patent publication WO2005/009956. One salt disclosed is(2S,4S)-1-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrilep-toluenesulfonic acid salt (also referred to as(2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrilep-toluenesulfonic acid salt, or Denagliptin tosylate). In someembodiments, the DPP-IV inhibitor is(2S,4S)-1-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrilep-toluenesulfonic acid salt:

Abbott disclosed a series of substituted pyrrolidinyl derivatives asDPP-IV inhibitors in international patent publication WO 2004/026822.Some embodiments of the present invention include every combination ofone or more compounds selected from the DPP-IV inhibitors disclosed inWO 2004/026822 and pharmaceutically acceptable salts, solvates, andhydrates thereof. One such compound is(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile.In some embodiments, the DPP-IV inhibitor is selected from(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Abbott has further disclosed a series of substitutedcyclohexanyl/cyclohexenyl derivatives as DPP-IV inhibitors ininternational patent publication WO 2007/027651. Some embodiments of thepresent invention include every combination of one or more compoundsselected from the DPP-IV inhibitors disclosed in WO 2007/027651 andpharmaceutically acceptable salts, solvates, and hydrates thereof. Onesuch compound is(1S,6R)-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohex-3-en-1-amine.In some embodiments, the DPP-IV inhibitor is selected from(1S,6R)-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohex-3-en-1-amine,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Biguanides

The biguanides are a class of drugs that stimulate anaerobic glycolysis,increase the sensitivity to insulin in the peripheral tissues, inhibitglucose absorption from the intestine, suppress of hepaticgluconeogenesis, and inhibit fatty acid oxidation. Examples ofbiguanides include phenformin ((phenylethyl)biguanide), metformin(dimethylbiguanide), buformin (butylbiguanide), proguanil(1-(p-chlorophenyl)-5-isopropylbiguanide), and biguanides known in theart.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a biguanide selected from the followingbiguanides and pharmaceutically acceptable salts, solvates, and hydratesthereof: (phenylethyl)biguanide, dimethylbiguanide, butylbiguanide,1-(p-chlorophenyl)-5-isopropylbiguanide.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a biguanide selected from (phenylethyl)biguanide(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a biguanide selected from dimethylbiguanide(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof; the chemical structure is as follows:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a biguanide selected from butylbiguanide(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof; the chemical structure is as follows:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a biguanide selected from1-(p-chlorophenyl)-5-isopropylbiguanide (chemical structure shown below)and pharmaceutically acceptable salts, solvates, and hydrates thereof;the chemical structure is as follows:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a biguanide selected from the followingbiguanides: metformin, phenformin, buformin, and proguanil. In someembodiments, the pharmaceutical agent or the second pharmaceutical agentis metformin. In some embodiments, the pharmaceutical agent or thesecond pharmaceutical agent is phenformin. In some embodiments, thepharmaceutical agent or the second pharmaceutical agent is buformin. Insome embodiments, the pharmaceutical agent or the second pharmaceuticalagent is proguanil.

Alpha-Glucosidase Inhibitors

Alpha-Glucosidase inhibitors belong to the class of drugs whichcompetitively inhibit digestive enzymes such as alpha-amylase, maltase,alpha-dextrinase, sucrase, etc. in the pancreas and or small intestine.The reversible inhibition by alpha-glucosidase inhibitors retard,diminish or otherwise reduce blood glucose levels by delaying thedigestion of starch and sugars. Some representative examples ofalpha-glucosidase inhibitors include acarbose((2R,3R,4R,5R)-4-((2R,3R,4R,5S,6R)-5-((2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-((1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-2-yloxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal),miglitol((2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol),voglibose((1S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetraol),and alpha-glucosidase inhibitors known in the art.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a alpha-glucosidase inhibitor selected from thefollowing alpha-glucosidase inhibitors and pharmaceutically acceptablesalts, solvates, and hydrates thereof:

(2R,3R,4R,5R)-4-((2R,3R,4R,5S,6R)-5-((2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-((1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-2-yloxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal;(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol;(1S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetraol.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a alpha-glucosidase inhibitor selected from(2R,3R,4R,5R)-4-((2R,3R,4R,5S,6R)-5-((2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-((1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-2-yloxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a alpha-glucosidase inhibitor selected from(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a alpha-glucosidase inhibitor selected from(1S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetraol(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is an alpha-glucosidase inhibitor selected from:acarbose, miglitol, and voglibose. In some embodiments, thepharmaceutical agent or the second pharmaceutical agent is acarbose. Insome embodiments, the pharmaceutical agent or the second pharmaceuticalagent is miglitol. In some embodiments, the pharmaceutical agent or thesecond pharmaceutical agent is voglibose.

Insulin and Insulin Analogues

The term “insulin analogue” refers to the naturally occurring humanhormone and insulin receptor ligands (i.e., synthetic insulinanalogues). Insulin receptor ligands are structurally different from thenatural human hormone, but have substantially the same activity as humaninsulin in terms of glycemic control. Examples of an insulin analogueinclude, NPH insulin (also known as Humulin N, Novolin N, NPH Lletin II,and insulin isophane), insulin lispro(28B-L-lysine-29B-L-proline-insulin, wherein insulin is human insulin),insulin aspart (28B-L-aspartic acid-insulin, wherein insulin is humaninsulin), insulin glulisine (3B-L-lysine-29B-L-glutamic acid-insulin,wherein insulin is human insulin), and insulin analogues known in theart.

NPH insulin is marketed by Eli Lilly and Company under the name HumulinN, and is considered as an intermediate-acting insulin analogue given tohelp control the blood sugar level of those with diabetes. Insulinlispro is marketed by Eli Lilly and Company under the name Humalog, andis considered a rapid acting insulin analogue. Insulin aspart ismarketed by Novo Nordisk and sold as NovoRapid. Insulin aspart isconsidered a fast acting insulin analogue. Insulin glulisine wasdeveloped by Sanofi-Aventis and is sold under the trade name Apidra.Insulin glulisine is considered a rapid acting insulin analogue butshorter duration of action compared to human insulin.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is an insulin analogue selected from NPH insulinand pharmaceutically acceptable salts, solvates, and hydrates thereof.In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is an insulin analogue selected from insulin lisproand pharmaceutically acceptable salts, solvates, and hydrates thereof.In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is an insulin analogue selected from insulin aspartand pharmaceutically acceptable salts, solvates, and hydrates thereof.In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is an insulin analogue selected from insulinglulisine and pharmaceutically acceptable salts, solvates, and hydratesthereof.

Sulfonylureas

The sulfonylureas are drugs which promote secretion of insulin frompancreatic beta cells by transmitting signals of insulin secretion viareceptors in the cell membranes. Examples of a sulfonylurea includetolbutamide (Orinase, N-(butylcarbamoyl)-4-methylbenzenesulfonamide);acetohexamide (Dymelor,4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide); tolazamide(Tolinase, N-(azepan-1-ylcarbamoyl)-4-methylbenzenesulfonamide);chlorpropamide (Diabinese,4-chloro-N-(propylcarbamoyl)benzenesulfonamide); glipizide (Glucotrol,N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide);glibenclamide, also known as glyburide (Diabeta, Micronase, Glynase,5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide);glimepiride (Amaryl,3-ethyl-4-methyl-N-(4-(N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide);gliclazide (Diamicron,N-(hexahydrocyclopenta[c]pyrrol-2(1H)-ylcarbamoyl)-4-methylbenzenesulfonamide);and sulfonylureas known in the art.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected from sulfonylureas andpharmaceutically acceptable salts, solvates, and hydrates thereof:

N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide);5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide;3-ethyl-4-methyl-N-(4-(N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected fromN-(butylcarbamoyl)-4-methylbenzenesulfonamide (chemical structure shownbelow) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected from4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide (chemical structureshown below) and pharmaceutically acceptable salts, solvates, andhydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected fromN-(azepan-1-ylcarbamoyl)-4-methylbenzenesulfonamide (chemical structureshown below) and pharmaceutically acceptable salts, solvates, andhydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected from4-chloro-N-(propylcarbamoyl)benzenesulfonamide (chemical structure shownbelow) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurca selected fromN-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected from5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected from3-ethyl-4-methyl-N-(4-(N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected fromN-(hexahydrocyclopenta[c]pyrrol-2(1H)-ylcarbamoyl)-4-methylbenzenesulfonamide(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurca selected from the followingsulfonylurcas and pharmaceutically acceptable salts, solvates, andhydrates thereof: glipizide, glimepiride, and glibenclamide. In someembodiments, the pharmaceutical agent or the second pharmaceutical agentis tolbutamide. In some embodiments, the pharmaceutical agent or thesecond pharmaceutical agent is acetohexamide. In some embodiments, thepharmaceutical agent or the second pharmaceutical agent is tolazamide.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is chlorpropamide. In some embodiments, thepharmaceutical agent or the second pharmaceutical agent is glipizide. Insome embodiments, the pharmaceutical agent or the second pharmaceuticalagent is glyburide. In some embodiments, the pharmaceutical agent or thesecond pharmaceutical agent is glimepiride. In some embodiments, thepharmaceutical agent or the second pharmaceutical agent is gliclazide.

SGLT2 Inhibitors

Sodium-glucose transporter-2 (SGLT2) inhibitors belong to the class ofdrugs which inhibit the protein SGLT2 and the reabsorption of glucose inthe kidney. The inhibition by SGLT2 inhibitors retard, diminish, orotherwise reduce the amount of glucose that is reabsorbed and thereforeis eliminated in the urine. Some representative examples of SGLT2inhibitors include dapagliflozin((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,Bristol-Myers Squibb and AstraZeneca), remogliflozin (ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1H-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methylcarbonate, GlaxoSmithKline), ASP1941 (Kotobuki/Astellas), canagliflozin((2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,Johnson & Johnson/Mitsubishi/Tanabe), ISIS 388626 (an antisenseoligonucleotide, Isis Pharmaceuticals), sergliflozin (ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-(4-methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methylcarbonate, GlaxoSmithKline), AVE2268((2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3-yloxy)tetrahydro-2H-pyran-3,4,5-triol,Sanofi-Aventis), BI10773 (Boehringer Ingelheim), CSG453 (Chugai/Roche),LX4211 (Lexicon), and SGLT2 inhibitors known in the art.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is an SGLT2 inhibitor selected from the followingSGLT2 inhibitors and pharmaceutically acceptable salts, solvates, andhydrates thereof:

(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1H-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methylcarbonate; ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-(4-methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methylcarbonate;(2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3-yloxy)tetrahydro-2H-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected from(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected from ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1H-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methylcarbonate (chemical structure shown below) and pharmaceuticallyacceptable salts, solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected from ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-(4-methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methylcarbonate (chemical structure shown below) and pharmaceuticallyacceptable salts, solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is an SGLT2 inhibitor selected from: dapagliflozin,remogliflozin, and sergliflozin. In some embodiments, the pharmaceuticalagent or the second pharmaceutical agent is dapagliflozin. In someembodiments, the pharmaceutical agent or the second pharmaceutical agentis remogliflozin. In some embodiments, the pharmaceutical agent or thesecond pharmaceutical agent is sergliflozin.

Astellas and Kotobuki disclosed a series of SGLT2 inhibitors ininternational patent publication WO2004/080990. Some embodiments of thepresent invention include every combination of one or more compoundsselected from compounds disclosed in WO2004/080990 and pharmaceuticallyacceptable salts, solvates, and hydrates thereof.

Aventis disclosed a series of SGLT2 inhibitors in international patentpublication WO2004/007517. Some embodiments of the present inventioninclude every combination of one or more compounds selected fromcompounds disclosed in WO2004/007517 and pharmaceutically acceptablesalts, solvates, and hydrates thereof. One such compound is(2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3-yloxy)tetrahydro-2H-pyran-3,4,5-triol.In some embodiments, the SGLT2 inhibitor is selected from(2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3-yloxy)tetrahydro-2II-pyran-3,4,5-triol,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Tanabe disclosed a series of SGLT2 inhibitors in international patentpublication WO2005/012326. Some embodiments of the present inventioninclude every combination of one or more compounds selected fromcompounds disclosed in WO2005/012326 and pharmaceutically acceptablesalts, solvates, and hydrates thereof. One such compound is(2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.In some embodiments, the SGLT2 inhibitor is selected from(2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Boehringer Ingelheim disclosed a series of SGLT2 inhibitors ininternational patent publication WO2005/092877. Some embodiments of thepresent invention include every combination of one or more compoundsselected from compounds disclosed in WO2005/092877 and pharmaceuticallyacceptable salts, solvates, and hydrates thereof.

Chugai disclosed a series of SGLT2 inhibitors in international patentpublication WO2006/080421. Some embodiments of the present inventioninclude every combination of one or more compounds selected fromcompounds disclosed in WO2006/080421 and pharmaceutically acceptablesalts, solvates, and hydrates thereof.

Lexicon disclosed a series of SGLT2 inhibitors in international patentpublication WO2008/109591. Some embodiments of the present inventioninclude every combination of one or more compounds selected fromcompounds disclosed in WO2008/109591 and pharmaceutically acceptablesalts, solvates, and hydrates thereof.

Meglitinides

The meglitinides promote secretion of insulin by binding to thepancreatic beta cells in a similar manner as sulfonylureas but at analternative binding site. Examples of meglitinides include NovoNordisk's repaglinide (Prandin,(S)-2-ethoxy-4-(2-(3-methyl-1-(2-(piperidin-1-yl)phenyl)butylamino)-2-oxoethyl)benzoicacid), nateglinide (Starlix,(R)-2-((1r,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropanoicacid), mitiglinide((S)-2-benzyl-4-((3aR,7aS)-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoicacid), and the like.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a meglitinide selected from the followingmeglitinides and pharmaceutically acceptable salts, solvates, andhydrates thereof:

(S)-2-ethoxy-4-(2-(3-methyl-1-(2-(piperidin-1-yl)phenyl)butylamino)-2-oxoethyl)benzoicacid;(R)-2-((1r,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropanoicacid;(S)-2-benzyl-4-((3aR,7aS)-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoicacid.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is(S)-2-ethoxy-4-(2-(3-methyl-1-(2-(piperidin-1-yl)phenyl)butylamino)-2-oxoethyl)benzoicacid (chemical structure shown below) and pharmaceutically acceptablesalts, solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected from(R)-2-((1r,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropanoic acid(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a sulfonylurea selected from(S)-2-benzyl-4-((3aR,7aS)-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoicacid (chemical structure shown below) and pharmaceutically acceptablesalts, solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a meglitinide selected from the followingmeglitinides: repaglinide, nateglinide, mitiglinide, andpharmaceutically acceptable salts, solvates, and hydrates thereof. Insome embodiments, the pharmaceutical agent or the second pharmaceuticalagent is a meglitinide selected from repaglinide and pharmaceuticallyacceptable salts, solvates, and hydrates thereof. In some embodiments,the pharmaceutical agent or the second pharmaceutical agent is ameglitinide selected from nateglinide and pharmaceutically acceptablesalts, solvates, and hydrates thereof. In some embodiments, thepharmaceutical agent or the second pharmaceutical agent is a meglitinideselected from mitiglinide and pharmaceutically acceptable salts,solvates, and hydrates thereof.

Thiazolidinediones

Thiazolidinediones belong to the class of drugs more commonly known asTZDs. These drugs act by binding to the nuclear receptor peroxisomeproliferator-activated receptor ganuna (PPARγ) activate transcription ofa number of specific genes leading to a decrease in insulin resistance.Examples of thiazolidinediones include rosiglitazone (Avandia,5-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione),pioglitazone (Actos,5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione),troglitazone (Rezulin,5-(4-((6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy)benzyl)thiazolidine-2,4-dione),rivoglitazone(5-(4-((6-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4-dione),ciglitazone(5-(4-((1-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione),and thiazolidinediones known in the art.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a thiazolidinedione selected from the followingthiazolidinediones and pharmaceutically acceptable salts, solvates, andhydrates thereof:

5-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione;5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;5-(4-((6-methoxy-1H-benzo[d]imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4-dione;5-(4-((1-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is5-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is5-(4-((6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy)benzyl)thiazolidine-2,4-dione(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is5-(4-((6-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4-dione(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is5-(4-((1-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione(chemical structure shown below) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a thiazolidinedione selected from rosiglitazoneand pharmaceutically acceptable salts, solvates, and hydrates thereof.In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a thiazolidinedione selected from pioglitazoneand pharmaceutically acceptable salts, solvates, and hydrates thereof.In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a thiazolidinedione selected from troglitazoneand pharmaceutically acceptable salts, solvates, and hydrates thereof.In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a thiazolidinedione selected from rivoglitazoneand pharmaceutically acceptable salts, solvates, and hydrates thereof.In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is a thiazolidinedione selected from ciglitazoneand pharmaceutically acceptable salts, solvates, and hydrates thereof.

Anti-Diabetic Peptide Analogues

Anti-diabetic peptide analogues are peptides that promote secretion ofinsulin by acting as an incretin mimetic, such as, GLP-1 and GIP.Examples of an anti-diabetic peptide analog include, exenatide,liraglutide, taspoglutide, and anti-diabetic peptides analogues know inthe art.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent is an anti-diabetic peptide analogue selected from:exenatide; liraglutide; and taspoglutide. In some embodiments, thepharmaceutical agent or the second pharmaceutical agent is exenatide. Insome embodiments, the pharmaceutical agent or the second pharmaceuticalagent is liraglutide. In some embodiments, the pharmaceutical agent orthe second pharmaceutical agent is taspoglutide.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent isL-histidylglycyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-leucyl-L-seryl-L-lysyl-L-glutaminyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-α-glutamyl-L-alanyl-L-valyl-L-arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-lysyl-L-asparaginylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L-serinamide(i.e., exenatide) and pharmaceutically acceptable salts, solvates, andhydrates thereof.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent isL-histidyl-L-alanyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-α-glutamylglycyl-L-glutaminyl-L-alanyl-L-alanyl-N6-[N-(1-oxohexadecyl)-L-α-glutamyl]-L-lysyl-L-α-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-arginylglycyl-L-arginyl-glycine(liraglutide) and pharmaceutically acceptable salts, solvates, andhydrates thereof.

In some embodiments, the pharmaceutical agent or the secondpharmaceutical agent isH₂N-His-2-methyl-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-2-methyl-Ala-Arg-CONH₂(taspoglutide)and pharmaceutically acceptable salts, solvates, and hydrates thereof.

Other Utilities

Another object of the present invention relates to radiolabeledcompounds of the present invention that would be useful not only inradio-imaging but also in assays, both in vitro and in vivo, forlocalizing and quantitating GPR119 receptors in tissue samples,including human and for identifying GPR119 receptor ligands byinhibition binding of a radiolabeled compound. It is a further object ofthis invention to develop novel GPR119 receptor assays of which comprisesuch radiolabeled compounds.

The present disclosure includes all isotopes of atoms occurring in thepresent compounds, intermediates, salts and crystalline forms thereof.Isotopes include those atoms having the same atomic number but differentmass numbers. One aspect of the present invention includes everycombination of one or more atoms in the present compounds,intermediates, salts, and crystalline forms thereof that is replacedwith an atom having the same atomic number but a different mass number.One such example is the replacement of an atom that is the mostnaturally abundant isotope, such as ¹H or ¹²C, found in one the presentcompounds, intermediates, salts, and crystalline forms thereof, with adifferent atom that is not the most naturally abundant isotope, such as2H or 3H (replacing ¹H), or ¹¹C, ¹³C, or ¹⁴C (replacing ¹²C). A compoundwherein such a replacement has taken place is commonly referred to asbeing an isotopically-labeled compound. Isotopic-labeling of the presentcompounds, intermediates, salts, and crystalline forms thereof can beaccomplished using any one of a variety of different synthetic methodsknow to those of ordinary skill in the art and they are readily creditedwith understanding the synthetic methods and available reagents neededto conduct such isotopic-labeling. By way of general example, andwithout limitation, isotopes of hydrogen include 2H (deuterium) and 3H(tritium). Isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C. Isotopes ofnitrogen include ¹³N and ¹⁵N. Isotopes of oxygen include ¹⁵O, ¹⁷O, and¹⁸C. An isotope of fluorine includes ¹⁸F. An isotope of sulfur includes³⁵S. An isotope of chlorine includes ³⁶Cl. Isotopes of bromine include⁷⁵Br, ⁷⁶Br, ⁷⁷Br, and ⁸²Br. Isotopes of iodine include ¹²³I, ¹²⁴I, ¹²⁵I,and ¹³¹I. Another aspect of the present invention includes compositions,such as, those prepared during synthesis, preformulation, and the like,and pharmaceutical compositions, such as, those prepared with the intentof using in a mammal for the treatment of one or more of the disordersdescribed herein, comprising one or more of the present compounds,intermediates, salts, and crystalline forms thereof, wherein thenaturally occurring distribution of the isotopes in the composition isperturbed. Another aspect of the present invention includes compositionsand pharmaceutical compositions comprising compounds as described hereinwherein the compound is enriched at one or more positions with anisotope other than the most naturally abundant isotope. Methods arereadily available to measure such isotope perturbations or enrichments,such as, mass spectrometry, and for isotopes that are radio-isotopesadditional methods are available, such as, radio-detectors used inconnection with HPLC or GC.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Drawings and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or a scarcer radio-isotope or nonradioactiveisotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. These synthetic methods, for example, incorporatingactivity levels of tritium into target molecules, are as follows:

A. Catalytic Reduction with Tritium Gas: This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]: This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters and the like.

C. Reduction with Lithium Aluminum Hydride [³H]: This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters and the like.

D. Tritium Gas Exposure Labeling: This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]: This procedure is usuallyemployed to prepare ( )-methyl or N-methyl (³H) products by treatingappropriate precursors with high specific activity methyl iodide (³H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions: This procedure transforms an aryl amineor a heteroaryl amine into a diazonium salt, such as a diazoniumtetrafluoroborate salt and subsequently to ¹²⁵I labeled compound usingNa¹²⁵I. A representative procedure was reported by Zhu, G-D. andco-workers in J. Org. Chem., 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols: This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labelled Compd. Radiopharm., 1999,42, S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I: This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)₄]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresentative procedure was reported by Le Bas, M.-D. and co-workers inJ. Labelled Compd. Radiopharm. 2001, 44, S280-S282.

A radiolabeled GPR119 receptor Compound of Formula (Ia) can be used in ascreening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radiolabeled Compoundof Formula (Ia) to a GPR119 receptor. Accordingly, the ability of a testcompound to compete with the radiolabeled Compound of Formula (Ia) forthe binding to a GPR119 receptor directly correlates to its bindingaffinity.

Certain labeled compounds of the present invention bind to certainGPR119 receptors. In one embodiment the labeled compound has an IC₅₀less than about 500 μM. In one embodiment the labeled compound has anIC₅₀ less than about 100 μM. In one embodiment the labeled compound hasan IC₅₀ less than about 10 μM. In one embodiment the labeled compoundhas an IC₅₀ less than about 1 μM. In one embodiment the labeled compoundhas an IC₅₀ less than about 0.1 μM. In one embodiment the labeledcompound has an IC₅₀ less than about 0.01 μM. In one embodiment thelabeled compound has an IC₅₀ less than about 0.005 μM.

Other uses of the disclosed receptors and methods will become apparentto those skilled in the art based upon, inter alia, a review of thisdisclosure.

Examples

The compounds of the invention and their syntheses are furtherillustrated by the following examples. The following examples areprovided to further define the invention without, however, limiting theinvention to the particulars of these examples. The compounds describedherein, supra and infra, are named according to AutoNom version 2.2,AutoNom 2000, CS ChemDraw Ultra Version 7.0.1, or CS ChemDraw UltraVersion 9.0.7. In certain instances literature names and/or common namesare used and it is understood that these names would be recognized bythose skilled in the art.

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on aBruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI(Broad Band Inverse) and z-gradient. Chemical shifts are given in partsper million (ppm) with the residual solvent signal used as reference.NMR abbreviations are used as follows: s=singlet, d=doublet, dd=doubletof doublets, ddd=doublet of doublet of doublets, dt=doublet of triplets,t=triplet, td=triplet of doublets, tt=triplet of triplets, q=quartet,m=multiplet, brs=broad singlet, brd=broad doublet, brt=broad triplet,brq=broad quartet.

Microwave irradiations were carried out using a Smith Synthesizer™ or anEmrys Optimizer™ (Biotage). Thin-layer chromatography (TLC) wasperformed on silica gel 60 F₂₅₄ (Merck), preparatory thin-layerchromatography (prep TLC) was preformed on PK6F silica gel 60 A 1 mmplates (Whatman) and column chromatography was carried out on a silicagel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation wasdone under reduced pressure on a Büchi rotary evaporator.

LCMS spec: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.

Example 1.1: Preparation of 5-Fluoropyrimidine-4,6-diol Method A

To a three-neck round-bottom flask equipped with an overhead stirrer,nitrogen flow, and reflux condenser, was added 25 wt % sodium methoxidein methanol (950 mL, 4.15 mol) and formamide (357 mL, 8.98 mol). Themixture was heated to about 64° C. To the reaction mixture was addeddiethyl 2-fluoromalonate (177 mL, 1.12 mol) using an addition funnelover 1 h. The reaction temperature was maintained at 64° C. for 72 h.The reaction mixture was allowed to cool to room temperature and thesolvent was removed under reduced pressure. The residue was cooled to 0°C. and slowly acidified with concentrated hydrochloric acid to pH 1-2resulting in the precipitation of the product. The product was filteredand washed with an ice cold aqueous 1 N HCl solution. The off-whitesolid was suspended in acetonitrile, filtered and dried in a vacuum ovento give 5-fluoropyrimidine-4,6-diol (170 g, 1.31 mol) as a lightbrown-pinkish solid which was used without further purification. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.57 (s, 2H), 8.25 (s, 1H).

Method B

To a three neck 5 L round bottom flask equipped with magnetic stirrer,nitrogen flow and reflux condenser, was charged the following: sodiummethoxide (25% NaOMe in Methanol) (1.425 L, 6.230 mol) and formamide(0.535 L, 13.5 mol) under nitrogen and heated to 64° C. To the reactionmixture diethyl 2-fluoromalonate (CAS #685-88-1, 0.266 L, 1.684 mol) wasadded slowly using an addition funnel (reaction exothermic). Thereaction was heated at 64° C. for 72 h. The reaction was cooled down toroom temperature and solvent was removed under reduced pressure. Theresidue was cooled to 0° C. by ice bath. The mixture was stirred andacidified slowly with 10 N HCl to pH˜1-2. The product precipitated outand was filtered. The product was washed with ice cold 1N HCl. Theoff-white solid was suspended in ACN, filtered and dried (vacuum oven)at 30° C. for 16 h to give 5-fluoropyrimidine-4,6-diol (349.4 g, 2.686mol, 160% yield) as a light brown-pinkish solid.5-Fluoropyrimidine-4,6-diol (CAS #106615-61-6, 600 g, 4.613 mol, 62%purity) was pulverized (sieved) and placed in a sintered glass funnel (4L coarse). The material was suspended in an ice cold solution of 0.5 MHCl (aq) and the material was suspended (for 5 min) and then filtered.The filter cake was then washed with 1.2 L of ACN, EtOAc and finallyhexanes. The solid was dried (vacuum oven) overnight to give5-fluoropyrimidine-4,6-diol (276.459 g, 2.125 mol, 74% yield) as apurple-pinkish solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.9 (s, 1H), 12.3(brs, 2H).

Example 1.2: Preparation of 4,6-Dichloro-5-fluoropyrimidine Method A

To a 500 mL three-neck round-bottom flask containing phosphorusoxychloride (45.3 mL, 487 mmol) was slowly added5-fluoropyrimidine-4,6-diol (20.0 g, 154 mmol) and the resultingreaction mixture was heated to 60° C. To the resulting slurry was slowlyadded N,N-dimethylaniline (42.2 mL, 331 mmol) over 4 h using a syringepump and the reaction mixture was stirred at 60° C. for 16 h. Thereaction mixture was cooled to room temperature and slowly added into amixture of brine and ice (400 ml) with stirring. The aqueous layer wasextracted with dichloromethane (2×250 mL). The combined organic layers(light amber) were washed with cold aqueous 6 N HCl solution (200 mL),dried over sodium sulfate, and filtered through a glass fiber paper byvacuum filtration and the solvent was removed under reduced pressure (noheat) to give 4,6-dichloro-5-fluoropyrimidine (13 g, 78 mmol, 50.6%yield) as an amber oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.62 (s, 1H).

Method B

To a 2 L three necked round bottom flask containing5-fluoropyrimidine-4,6-diol (276.459 g, 2.125 mol) was added at roomtemperature slowly phosphoryl chloride (0.593 L, 6.376 mol) to form aslurry. To this slurry was added N,N-dimethylaniline (81 mL, 0.638 mol)very slowly using an addition funnel (exothermic) and the reaction wascontinued for 6 h at 110° C. After 6 h, the reaction mixture was cooledto room temperature and slowly added into brine and ice (2 L) withstirring. The aqueous layer (red) was extracted with DCM (2×2 L). Thecombined organic layers were washed with cold 6 N HCl (honey brown) (2×1L) and washed with sat NaHCO₃ (1 L). The organic layer was dried(Na₂SO₄), filtered by vacuum filtration through a glass fiber paper andsolvent was removed under reduced pressure (no heat) to give4,6-dichloro-5-fluoropyrimidine (CAS #213265-83-9, 347.9 g, 2.084 mol,98% yield) as an amber oil. NMR showed the oil contained traces of DCM.4,6-Dichloro-5-fluoropyrimidine (420 g, 2.515 mol) was distilled byvacuum distillation to give 4,6-dichloro-5-fluoropyrimidine (332.574 g,1.992 mol, 79% yield) as a colorless oil. The product solidified in theflask at −78° C. and melts when brought to room temperature. Conditionsfor distillation: Oil Bath: 100° C.; Product boiling temp: 35° C.;Pressure: 1 Torr. H NMR (400 MHz, DMSO-d₆) δ ppm 8.8 (s, 1H).

Example 1.3: Preparation of 2-Fluoro-2-methylpropanenitrile Method A

To a 1 L three-neck round-bottom flask containing2-hydroxy-2-methylpropanenitrile (120 mL, 1.31 mol) at 4° C. was slowlyadded (diethylamino)sulfur trifluoride (DAST) (172 mL, 1.31 mol) over 1h via an additional funnel. The reaction mixture was allowed to warm toroom temperature and stirred overnight. The mixture was directlypurified by vacuum distillation (40-45° C./45 mmHg) to provide2-fluoro-2-methylpropanenitrile (83.36 g, 0.957 mol, 73.0% yield) as acolorless oil containing methacrylonitrile (˜10%). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.77 (d, J=20 Hz, 6H).

Method B

2-Hydroxy-2-methylpropanenitrile (CAS #75-86-5, 221 mL, 2.420 mol) wascooled down to −10° C. (ice/acetone/dry ice) in a 1 L three necked roundbottomed flask and DAST (246 mL, 1.861 mol) was added slowly using anaddition funnel over a period of 2 h. Once the addition was finished,the reaction was allowed to warm up to room temperature and stirredovernight. The product was distilled by vacuum distillation (30° C., 4Torr) to give 2-fluoro-2-methylpropanenitrile (CAS #138999-34-5, 148.65g, 1.707 mol, 92% yield) as colorless oil. The titled compound turned anamber color if not protected from light. Final product containedcontaining methacrylonitrile (NMR estimate-10%). ¹H NMR (400 MHz, CDCl₃)δ ppm 1.8 (d, 6H).

Example 1.4: (Z)-2-Fluoro-N′-hydroxy-2-methylpropanimidamide Method A

To a 1 L round-bottom flask was added 2-fluoro-2-methylpropanenitrile(80.7 g, 0.927 mol) and in ethanol (400 mL). To the resulting solutionwas slowly added a 50% aqueous solution of hydroxylamine (81.0 mL, 1.32mol) via an additional funnel. The mixture was heated at 60° C. for 3 h.The mixture was allowed to cool to room temperature and ethanol wasremoved under reduced pressure. The residue was dissolved indichloromethane (200 mL) and the organic layer was washed with water(2×200 mL) and brine solution (200 mL). The aqueous layer was backextracted with dichloromethane. The combined organics were dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure to provide(Z)-2-fluoro-N-hydroxy-2-methylpropanimidamide (60.0 g, 0.499 mol, 53.9%yield) as an off-white solid. Exact mass calculated for C₄H₉FN₂O:120.07, found: LCMS m/z=121.0 (M+H⁺)(M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δppm 1.58 (d, J=24 Hz, 6H), 4.64 (brs, 1H), 4.81 (brs, 2H).

Method B

2-Fluoro-2-methylpropanenitrile (148.65 g, 1.707 mol) was taken up inEtOH (700 mL) and hydroxylamine 50% water by weight (135 g, 2.048 mol)was added very slowly keeping the temperature at around 35° C. then thereaction mixture was heated to 80° C. for 16 h in a 1 L round bottomedflask. After 16 h the reaction mixture was cooled to room temp andsolvent was removed under reduced pressure. The residue was taken up inDCM (500 mL) with slight heating and the solids that did not dissolvewere decanted. The DCM was removed under reduced pressure to give(Z)-2-fluoro-N-hydroxy-2-methylpropanimidamide 127 g, as a light yellowsolid. The solid was sublimed at 100° C. and 3 Torr to give(Z)-2-fluoro-N′-hydroxy-2-methylpropanimidamide (74 g, 0.616 mol, 36.1%yield) as a white solid. The final product contained about 7% (NMRestimate) of the elimination side product (CAS #339075-08-0).

(Z)-2-fluoro-N′-hydroxy-2-methylpropanimidamide (120 g, 999 mmol) waspurified by recrystallization from MTBE. The material was dissolved inMTBE, 5×-10× by volume. The solution was then cooled to −78° C. usingdry ice and acetone. The resulting precipitate was collected by vacuumfiltration and washed with cold MTBE to give(Z)-2-fluoro-N′-hydroxy-2-methylpropanimidamide (114.019 g, 949 mmol,95% yield) as a white solid. The title compound contained about 1% byNMR of (Z)—N′-hydroxymethacrylimidamide. Mp: 101.9° C.; ¹H NMR (400 MHz,CDCl3) δ ppm 1.6 (d, 6H), 4.75 (brs, 2H), 7.55 (brs, 1H).

Example 1.5: Preparation of tert-Butyl4-(3-(2-Fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate

To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (85g, 372 mmol) in acetonitrile (450 ml) was addeddi(1H-imidazol-1-yl)methanone (72.4 g, 447 mmol) at room temperature andthe reaction mixture was heated at 45° C. for 1 h. The reaction wasmonitored by negative mode LC/MS. The reaction mixture was cooled downto room temperature and (Z)-2-fluoro-N′-hydroxy-2-methylpropanimidamide(44.7 g, 372 mmol) was added. The reaction mixture was stirred at roomtemperature for 1.5 h and the volatile organics were removed undervacuum. The residue was poured into a cold aqueous 1 M HCl solution (500mL). The aqueous phase was extracted with ethyl acetate (3×250 mL). Theorganic layers were combined and rinsed with aqueous 1 M HCl solution(3×150 mL). The organic layers were combined and washed with saturatedNaHCO₃ solution (2×100 mL) and brine. The organic phase was dried oversodium sulfate, filtered, and concentrated under reduced pressure togive (Z)-tert-butyl4-(2-fluoro-1-(hydroxyimino)-2-methylpropylcarbamoyl)piperidine-1-carboxylate(114 g, 344 mmol, 92% yield) as a white solid.

A flask, containing (Z)-tert-butyl4-(2-fluoro-1-(hydroxyimino)-2-methylpropylcarbamoyl)piperidine-1-carboxylate,was heated in a heating mantle at 115° C. for 16 h under reducedpressure. The reaction mixture was further dried at 50° C. under reducedpressure to give tert-butyl4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate(94 g, 300 mmol, 81% yield) as a thick amber oil. Exact mass calculatedfor C₁₅H₂₄FN₃O₃: 313.37, found: LCMS m/z=314.2 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 1.46 (s, 9H), 1.75 (s, 3H), 1.77-1.90 (m, 5H), 2.02-2.11(m, 2H), 2.89-3.01 (m, 2H), 3.06-3.16 (m, 1H), 4.04-4.14 (m, 2H).

Example 1.6: Preparation of tert-Butyl4-(3-(2-Fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylateHydrochloride

To a mixture of 4 M HCl solution in dioxane (244 mL, 975 mmol) cooled to0° C. (external ice bath) was added tert-butyl4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate(94 g, 300 mmol). The ice bath was removed and the reaction mixture wasstirred at room temperature for 1 h. The reaction was monitored byLC/MS. The volatile organics were removed under reduced pressure to givea yellowish solid. The solids were triturated with tert-butyl methylether (MTBE) and collected by filtration to give3-(2-fluoropropan-2-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazolehydrochloride (70.1 g, 281 mmol, 94% yield) as a white solid. Exact masscalculated for C₁₀H₁₇ClFN₃O: 213.2, found: LCMS m/z=214.0 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.71-1.77 (d, J=20 Hz, 6H), 1.90-2.01 (m, 2H),2.18-2.25 (m, 2H), 3.00-3.09 (m, 2H), 3.30-3.37 (m, 2H), 3.42-3.50 (m,1H), 8.85 (brs, 1H), 9.02 (brs, 1H).

Example 1.7: Preparation of5-(1-(6-Chloro-5-fluoropyrimidin-4-yl)piperidin-4-yl)-3-(2-fluoropropan-2-yl)-1,2,4-oxadiazoles

To a suspension of3-(2-fluoropropan-2-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazolehydrochloride (45.0 g, 180 mmol) in acetonitrile was addeddiisopropylethylamine (94 mL, 541 mmol), followed by4,6-dichloro-5-fluoropyrimidine (18.81 mL, 180 mmol). The reactionmixture was stirred at 40° C. for 1 h. The volatile organics wereremoved under vacuum to give a thick amber oil. The oil was poured intowater and the product was extracted with ethyl acetate (2×250 mL). Theorganic layers were combined, dried over sodium sulfate, filtered, andconcentrated under reduced vacuum to give a yellowish solid. This solidwas purified by Biotage™ column chromatography (hexane:ethyl acetategradient) to give5-(1-(6-chloro-5-fluoropyrimidin-4-yl)piperidin-4-yl)-3-(2-fluoropropan-2-yl)-1,2,4-oxadiazole(40.4 g, 118 mmol, 65.2% yield) as a white solid. Exact mass calculatedfor C₁₄H₁₆ClF₂N₅₀: 343.76, found: LCMS m/z=344.2 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 1.77-1.81 (d, J=20 Hz, 6H), 1.98-2.07 (m, 2H),2.20-2.27 (m, 2H), 3.28-3.35 (m, 3H), 4.48-4.54 (m, 2H), 8.17 (s, 1H).

Example 1.8: Preparation of 4-Amino-3-fluoro-N,N-dimethylbenzamideMethod A

To a three-neck round-bottom flask, equipped with a mechanical stirrer,thermometer, and addition funnel, was added 4-amino-3-fluorobenzoic acid(40 g, 258 mmol), dimethylamine (520 ml, 1.04 mol), and dichloromethane(1 L). The reaction mixture was cooled in an ice-bath and1-propanephosphonic acid cyclic anhydride (250 g, 393 mmol) was slowlyadded by addition funnel. After 1 h, the addition was complete andmixture was allowed to warm up to room temperature. After stirringovernight, the solution was concentrated under reduced pressure and theresidue was extracted with dichloromethane and washed with an aqueous 2M NaOH solution. The organic phases were dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by Biotage™ column chromatography (hexane:ethyl acetategradient) to give 4-amino-3-fluoro-N,N-dimethylbenzamide (31.9 g, 175mmol, 67.9% yield) as a tan solid. Exact mass calculated for C₉H₁₁FN₂O182.2, found: LCMS m/z=183.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.05(s, 6H), 3.91 (brs, 2H), 6.76 (t, J=10 Hz, 1H), 7.07 (dt, J=8.15, 0.85Hz, 1H), 7.13 (dd, J=11.43, 1.83 Hz, 1H).

Method B

4-Amino-3-fluorobenzoic acid (CAS #455-87-8, 221.85 g, 1.402 mol) wassuspended in acetonitrile (1.80 L). To this suspension was addeddi(1H-imidazol-1-yl)methanone (250 g, 1.542 mol) at room temperature andthe reaction bubbled and became a clear solution. The reaction mixturewas cooled down to 0° C. then N-ethyl-N-isopropylpropan-2-amine (0.416L, 2.383 mol) was added followed by dimethylamine hydrochloride (137 g,1.682 mol). The reaction mixture was allowed to stir at room temp for 30min. LCMS showed the reaction was complete. The solvent was removedunder reduced pressure. The residue was taken up in DCM (2 L) and washedwith 1 M HCl (2×2 L). The separation of the layers was difficult toobserve due to the presence of some solids. The resulting mixture wasfiltered and the layers separated. The aqueous layer was back extractedwith DCM (2×2 L). The organic layers were combined and dried (Na₂SO₄),filtered by vacuum filtration through a sintered glass funnel andsolvent was removed under reduced pressure to give 270 g of a dark brownsolid. To this solid was added a mixture of 2:1 toluene:hexane (2000 mL)and the mixture was heated to 45° C. to form a slurry. The resultingprecipitate was collected by vacuum filtration and washed with 1:1toluene:hexane (2 L) and with hexane (2 L). The resulting solid wasdried (vacuum oven). The filtrate contained some of the product and thesolvent was removed under reduced pressure and the slurry was repeated.The first batch was 196 g and the 2^(nd) batch contained 32.528 g. Bothbatches were the same by NMR and LC/MS and were combined to give4-amino-3-fluoro-N,N-dimethylbenzamide (CAS #536748-06-8, 228.93 g,1.257 mol, 90% yield) as a light brown solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.9 (s, 6H), 5.5 (s, 2H), 6.8 (t, 1H), 7.0 (dd, J=8.21, 1.9 Hz,1H), 7.1 (dd, J=12.13, 1.8 Hz, 1H). Exact mass calculated for C₉H₁₁FN₂O182.2, found: LCMS m/z=183.2 [M+H]⁺).

Example 1.9: Preparation of Ethyl1-(6-Chloro-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate

To a three neck 5 L round bottom flask equipped with magnetic stirrer,and nitrogen flow, was charged the following:4,6-dichloro-5-fluoropyrimidine (332.574 g, 1.992 mol) with the aid ofAcetonitrile (2.6 L). The following were combined in an additionalfunnel: ethyl piperidine-4-carboxylate (CSA #1126-09-6, 0.316 L, 1.992mol) and DIEA (0.522 L, 2.988 mol). The contents of the addition funnelwere added slowly to the flask (exothermic). The addition funnel wasrinsed with ACN. An LC/MS taken 30 min after completion of the additionand the reaction was determined to be complete. The solvent was removedunder reduced pressure to obtain an oil residue. The residue was takenup in EtOAc (3.0 L) and washed with 1M HCl (2×2.0 L), washed with satNaHCO₃ (1×2.0 L) and washed with sat NaCl (1 L). The organic layer wasdried (Na₂SO₄), filtered by vacuum filtration through a glass fiberpaper and solvent was removed under reduced pressure to give ethyl1-(6-chloro-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate (586.2 g,2.037 mol, 102% yield) as a light yellow oil which was used withoutfurther purification. The title compound contained some EtOAc by NMR.Exact mass calculated for C₁₂H₁₅ClFN₃O₂ 287.08, found: LCMSm/z=288.4/290.2 [M+H]⁺); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.2 (t, J=7.1Hz, 3H), 1.6 (q, J=13.6, 3.8 Hz, 2H), 1.9 (dd, J=13.5, 3.7 Hz, 2H),2.7-2.8 (m, 1H), 3.2-3.3 (m, 2H), 4.1 (q, J=7.2 Hz, 2H), 4.3 (d, 2H),8.2 (d, J=1.5 Hz, 1H).

Example 1.10: Preparation of Ethyl1-(6-(4-(Dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate

To a three neck 5 L round bottom flask equipped with overhead stirrer,nitrogen flow, and reflux condenser, was charged the following under N2:ethyl 1-(6-chloro-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate (362g, 1.257 mol), 4-amino-3-fluoro-N,N-dimethylbenzamide (229 g, 1.257mol), 1,1′-bis(di-t-butylphosphino)ferrocene (59.6 g, 126 mmol), cesiumcarbonate (491 g, 1.508 mol) and diacetoxypalladium (14.11 g, 62.8 mmol)with the aid of dioxane (2 L). The mixture was heated to 102° C. for 2h. After 2 h the reaction was complete by LC/MS. The reaction mixturewas allowed to cool down to room temperature. The mixture was dilutedwith EtOAc (2 L) and treated with a small amount of charcoal. This crudemixture was filtered through a pad of silica gel (12 cm height in 6 Lfilter funnel) and rinsed with additional EtOAc (6×2 L). The filtratewas concentrated under reduced pressure to dryness and dried under highvacuum to give ethyl1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate(520.02 g, 1.2 mol, 95% yield) as a brown solid. Exact mass calculatedfor C₂₁H₂₅F₂N₅O3 433.19, found: LCMS m/z=434.4 [M+H]⁺). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.2 (t, J=7.2 Hz, 3H), 1.5-1.7 (m, 2H), 1.9 (dd, J=13.3,3.4 Hz, 2H), 2.61-2.71 (m, 1H), 3.0 (s, 6H), 3.1 (t, J=11.2 Hz, 2H),4.08 (q, J=7.07 Hz, 2H), 4.2 (d, J=13.4 Hz, 2H), 7.2 (dd, J=8.1, 1.5 Hz,1H), 7.30 (dd, J=11.1, 1.8 Hz, 1H), 7.6 (t, J=8.1 Hz, 1H), 7.9 (d, J=1.8Hz, 1H), 8.8 (s, 1H).

Example 1.11: Preparation of1-(6-(4-(Dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylicAcid

To a three neck 5 L round bottom flask equipped with overhead stirrerand reflux condenser, was charged the following: ethyl1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate(260 g, 0.6 mol) and triethylamine (251 mL, 1.8 mol) with the aid ofMeCN (2 L) and water (40.8 mL). To this was added lithium bromide (521g, 5.998 mol) portion wise (exothermic) maintaining the internaltemperature under 50° C. The mixture was heated at 75° C. for 16 h. Themixture was filtered and the solid was washed with MeCN (2×1 L). Thesolid was dissolved in hot water (2 L) and the solution was cooled in anice-bath. To the cold mixture was slowly added 10 N HCl (aqueous) byusing dropping funnel to pH 1. The resulting precipitate was collectedby vacuum filtration, washed with 1N HCl (aqueous) (1 L), and dried inan oven at 45° C. and under high vacuum to afford1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylicacid (231 g, 0.570 mol, 95% yield) as a light brown solid. Exact masscalculated for C₁₉H₂₁F₂N₅O₃ 405.16, found: LCMS m/z=406.4 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.5-1.7 (m, 2H), 1.9 (dd, J=13.4, 3.0 Hz, 2H),2.5-2.6 (m, J=10.8, 10.8, 4.0, 3.9 Hz, 1H), 3.0 (s, 6H), 3.1 (t, J=11.2Hz, 2H), 4.2 (d, J=13.39 Hz, 2H), 7.2 (dd, J=8.2, 1.6 Hz, 1H), 7.3 (dd,J=10.9, 1.8 Hz, 1H), 7.6 (t, J=8.1 Hz, 1H), 8.0 (d, J=1.3 Hz, 1H), 9.1(brs, 1H), 11.3 (brs, 1H).

Example 1.12: Preparation of3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Compound 1) Method A

To a suspension of5-(1-(6-chloro-5-fluoropyrimidin-4-yl)piperidin-4-yl)-3-(2-fluoropropan-2-yl)-1,2,4-oxadiazole(1.0 g, 2.91 mmol) and 4-amino-3-fluoro-N,N-dimethylbenzamide (0.530 g,2.91 mmol) in dioxane (9 mL) was added palladium(II) acetate (0.131 g,0.582 mmol), 1,1′-bis(di-t-butylphosphino)ferrocene (0.552 g, 1.164mmol), and cessium carbonate (3.32 g, 10.18 mmol) under nitrogen. Thesuspension was heated gradually to 95° C. in an oil bath and stirred atthis temperature for 1 h. The reaction was quenched with water and themixture was extracted with ethyl acetate. The organic layer was washedwith water (2×50 mL), dried over magnesium sulfate, filtered,concentrated under reduced pressure, and purified by Biotage™ columnchromatography (hexane:ethyl acetate gradient) to give3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(0.715 g, 1.461 mmol, 50.2% yield) as a light yellow solid. Exact masscalculated for C₂₃H₂₆F₃N₇O₂: 489.5, found: LCMS m/z=490.4 [M+H]⁺; ¹H NMR(400 MHz, CDCl3) δ ppm 1.79 (d, J=20 Hz, 6H), 2.02 (dd, J=13.83, 3.85Hz, 2H), 2.21 (dd, J=13.52, 3.66 Hz, 2H), 3.07 (brs, 6H), 3.19-3.40 (m,3H), 4.36-4.56 (m, 2H), 6.86-7.02 (m, 1H), 7.18-7.32 (m, 2H), 8.14 (d,J=1.26 Hz, 1H), 8.55 (t, J=8.46 Hz, 1H).

Method B

To a three neck 5 L round bottom flask equipped with an overhead stirrerand nitrogen flow was charged the following:1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylicacid (340 g, 0.839 mol) and di(1H-imidazol-1-yl)methanone (143 g, 0.881mol) with the aid of MeCN (2 L). After 5 min the reaction mixture becamehomogeneous. The reaction was allowed to continue for 30 min. LCMS att=30 min (455.46 [M+H]⁺) showed the activated acid reaction wascomplete. To the resulting mixture was added(Z)-2-fluoro-N′-hydroxy-2-methylpropanimidamide (106 g, 0.881 mol) andthe reaction mixture was allowed to continue for 16 h. After 16 h theresulting precipitate was collected by vacuum filtration. The solid waswashed with MeCN (2 L), followed by MTBE (2 L) and Hexane (2 L) anddried (vacuum oven) high vacuum and no heat to give(E)-1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4-yl)-N-(2-fluoro-1-(hydroxyimino)-2-methylpropyl)piperidine-4-carboxamide(330 g, 650 mmol, 78% yield) as an off-white solid. Exact masscalculated for C₂₃H₂₈F₃N₇O₃ 507.22, found: LCMS m/z=508.2 [M+H]⁺); ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.7 (s, 3H), 1.8 (s, 3H), 1.8-1.9 (m, 2H),2.1 (dd, J=13.1, 2.8 Hz, 2H), 3.0 (s, 6H), 3.2-3.3 (m, 2H), 3.4-3.5 (m,J=11.0, 11.0, 4.0, 3.9 Hz, 1H), 4.3 (d, J=13.4 Hz, 2H), 7.2 (dd, J=8.2,1.6 Hz, 1H), 7.3 (dd, J=11.0, 1.6 Hz, 1H), 7.6 (t, J=8.1 Hz, 1H), 7.9(d, J=1.5 Hz, 1H), 8.8 (s, 1H).

The filtrate still contained some product by LC/MS. The solvent wasremoved under reduced pressure to give a black oil (250 g). The blackoil was not combined with the solid but was instead heated to 90° C.under house vacuum for 16 h. After 16 h the reaction was complete andthe solvent was removed under reduced pressure. The residue was dilutedwith EtOAc and passed through a silica plug using a 2 L coarse funnelwith a 14 cm diameter and filled with 7 cm of silica. The product waseluted with 2 L of EtOAc to give 36 g of a pinkish solid. The solid wastriturated with MTBE to give3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(19.2 g, 39.2 mmol, 4.68% yield) as a off-white solid, crop 2.

(E)-1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4-yl)-N-(2-fluoro-1-(hydroxyimino)-2-methylpropyl)piperidine-4-carboxamide(330 g, 650 mmol) was transferred to a 2 L round bottom flask and DMA(500 mL) was added. The reaction was heated to 110° C. for 4 h. Thereaction was complete by LC/MS. The reaction was allowed to cool down toroom temperature and diluted with MeCN. The resulting precipitate wascollected by vacuum filtration to give3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(250 g, 511 mmol, 60.9% yield) as a white solid (crop 1). The filtratestill contained some product. The DMA and MeCN were removed underreduced pressure and the resulting precipitate was triturated with MTBEto give3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(96 g, 196 mmol, 23.38% yield) as a light brown solid (crop 3). All thecrops of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamidecontained less then 6% of the starting material1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylicacid. To remove the starting material, each crop was dissolved (crop 2and crop 3 were combined) in DMA (500 mL for crop 1, and 230 mL forcombined crop 2,3) at 100° C. Once the solid was dissolved, aqueoussaturated NaHCO₃ (500 mL, for crop 1, and 230 mL for combined crop 2,3)was gently added to crash out the product. The mixture was diluted withDI water (1.250 L for crop 1, and 0.576 L for combined crop 2,3). Themixture was allowed to cool down to room temperature and the resultingprecipitate was collected by vacuum filtration and washed with water togive 200 g as an off white solid (from crop 1) and 92.8 g as a lightbrown solid (from crop 2,3) for a total of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(292.8 g, 598 mmol, 71.3% yield).

3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(281.8 g, 576 mmol) was taken up in DMA (600 mL) and heated to 100° C.in a 5 L three necked round bottomed flask attached to a mechanicalstirrer. After all the solids went into solution, DI water (600 mL) wasadded gently. The reaction was then diluted with more DT water (1800 ml)to bring the total volume to 10× by weight. The resulting precipitatewas collected by vacuum filtration and washed with water. The cake wasallowed to dry under house vacuum on the fritted funnel. When the cakewas mostly dried, it was dried further (vacuum oven) at 45° C. underhigh vacuum overnight to give3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(279.4 g, 571 mmol, 99% yield) as a tan solid.

Example 1.13: Preparation of3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide(Compound 2) Step A: Preparation of Ethyl3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzoate

A suspension of5-(1-(6-chloro-5-fluoropyrimidin-4-yl)piperidin-4-yl)-3-(2-fluoropropan-2-yl)-1,2,4-oxadiazole(1.0 g, 2.91 mmol), ethyl 4-amino-3-fluorobenzoate (0.533 g, 2.91 mmol),diacetoxypalladium (0.098 g, 0.436 mmol), 1,1′-bis(di-t-butylphosphino)ferrocene (0.414 g, 0.873 mmol), and Cs₂CO₃ (2.464g, 7.56 mmol) in dioxane (10 mL) was heated conventionally at 85° C. for1 h. Reaction was quenched with water and extracted with AcOEt. Theorganic layer was concentrated to give a residue and the residue waspurified by prep-HPLC. Fractions containing desired product werecombined, basified with saturated NaHCO₃ (aq), partially concentratedunder vacuum, and extracted with AcOEt. The organic layer was rinsedwith brine, dried over sodium sulfate, filtered, and concentrated togive the title compound (1.0 g, 2.039 mmol, 70% yield). Exact masscalculated for C₂₃H₂₅F₃N₆O₃: 490.2, found: LCMS m/z=491.3 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 1.39 (t, J=7.07 Hz, 3H), 1.77 (s, 3H), 1.82 (s,3H), 1.97-2.08 (m, 2H), 2.17-2.25 (m, 2H), 3.22-3.33 (m, 3H), 4.37 (q,J=7.07 Hz, 2H), 4.42-4.50 (m, 2H), 7.04-7.10 (m, 1H), 7.78 (dd, J=11.87,1.89 Hz, 1H), 7.84-7.89 (m, 1H), 8.15-8.18 (m, 1H), 8.66 (t, J=8.46 Hz,1H).

Step B: Preparation of3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzoicAcid

To a solution of ethyl3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzoate(440 mg, 0.897 mmol) in a mixed solvent of MeOH (15 mL) and THF (5.0 mL)was added lithium hydroxide hydrate (188 mg, 4.49 mmol) and Water (5.0mL). The mixture was stirred at room temperature overnight. The mixturewas acidified with 1N HCl (aq) to pH 2-3 and concentrated in vacuo toremove the organic solvents. The solid was collected by vacuumfiltration to give the title compound (394.3 mg, 0.853 mmol, 95% yield).Exact mass calculated for C₂₁H₂₁F₃N₆O₃: 462.2, found: LCMS m/z=463.4[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.77 (s, 3H), 1.82 (s, 3H),1.98-2.07 (m, 2H), 2.19-2.23 (m, 2H), 3.23-3.34 (m, 3H), 4.43-4.51 (m,2H), 7.16-7.20 (m, 1H), 7.83 (dd, J=11.87, 1.89 Hz, 1H), 7.90-7.94 (m,1H), 8.17-8.19 (m, 1H), 8.71 (t, J=8.34 Hz, 1H), —OH was not observed.

Step C: Preparation of3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide(Compound 2)

To a solution of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzoicacid (73 mg, 0.158 mmol) and HATU (70 mg, 0.184 mmol) in DMF (2 mL),methanamine (315 μL, 0.630 mmol) was added. After stirring at roomtemperature for 1 h, mixture was purified by HPLC (5-95% CH₃CN).Fractions containing desired product were partly concentrated andresidue was extracted with 1M NaOH and CH₂Cl₂. Organic phases were driedover MgSO₄, filtered, and concentrated to give the title compound (51.9mg, 0.109 mmol, 69% yield). Exact mass calculated for C₂₂H₂₄F₃N₇O₂:475.2, found: LCMS m/z=476.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.77(s, 3H), 1.82 (s, 3H), 1.98-2.07 (m, 2H), 2.19-2.23 (m, 2H), 3.02 (d,J=4.80 Hz, 3H), 3.23-3.31 (m, 3H), 4.43-4.48 (m, 2H), 6.04-6.05 (m, 1H),7.00-7.02 (m, 1H), 7.47-7.50 (m, 1H), 7.62 (dd, J=11.87, 1.89 Hz, 1H),8.15 (d, J=1.39 Hz, 1H), 8.61 (t, J=8.34 Hz, 1H).

Example 1.14: Preparation of3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzamide(Compound 3)

To a suspension of3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzoicacid (see Example 1.13, Step B, 50 mg, 0.108 mmol), ammonium chloride(17.35 mg, 0.324 mmol), and HATU (61.7 mg, 0.162 mmol) in DMF (2 mL) ina sealed tube was added N-ethyl-N-isopropylpropan-2-amine (0.094 mL,0.541 mmol). The mixture was stirred at RT for 1 hr. The mixture wasdirectly purified by prep HPLC. Pure fractions were combined,neutralized with saturated NaHCO₃ (aq), and evaporated MeCN to form asolid. The solid was collected by vacuum filtration to afford the titlecompound (22.5 mg, 0.049 mmol, 45.1% yield) as a white solid. Exact masscalculated for C₂₁H₂₂F₃N₇O₂: 461.2, found: LCMS m/z=462.4 (M+H⁺); ¹H NMR(400 MHz, CDCl₃) δ ppm 1.80 (d, J=21.5 Hz, 6H), 2.00-2.07 (m, 2H),2.19-2.23 (m, 2H), 3.23-3.32 (m, 3H), 4.44-4.49 (m, 2H), 5.74 (bs, 2H),7.06 (t, J=3.7 Hz, 1H), 7.55 (dd, J=8.6, 1.6 Hz, 1H), 7.66 (dd, J=11.9,2.0 Hz, 1H), 8.16 (d, J=1.4 Hz, 1H), 8.66 (t, J=8.3 Hz, 1H).

Example 2: In Vivo Effects of3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Compound 1) on Glucose Homeostasis in Male Diabetic ZDF Rats (OralGlucose Tolerance Test (oGTT))

Male ZDF rats were fasted for 18 h and randomly grouped (n=6) to receivea GPR119 agonist, (Compound 1), at 0.3, 3, 10, or 30 mg/kg (mg compoundper kg body weight). The compound was delivered orally via a gavageneedle (p.o., volume 4 ml/kg) 60 min prior to glucose bolus (3 g/kg)(time=−60 min in FIG. 1), with a separate group receiving vehicle (20%hydroxypropyl-beta-cyclodextrin) as control. At time 0 min the glucosebolus was administered. Levels of blood glucose were assessed using aglucometer (One-Touch Ultra™, LifeScan) at time −60 minute (prior tocompound administration), at 0 min (at time when glucose bolus wasgiven), and at 30, 60, 90, and 120 min post glucose bolus. The plasmaglucose concentration (mg/dL) at the different time points is shown inFIG. 1 and Table 1. Glucose excursion (AUC (area under the curve)reduction) in compound treated animals relative to vehicle control isshown in FIG. 2 and Table 2. These results demonstrated that the GPR119agonist,3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Compound 1), lowered blood glucose after a challenge with glucose indiabetic ZDF rats.

TABLE 1 Plasma Glucose (mg/dL) Compound 1 Dose (mg/kg) Time 20% HPCD 0.33.0 10.0 30.0 (min) Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM −60106.7 3.2* 106.3 5.7* 110.0 5.2* 108.7 3.1* 104.8 4.8* 0 93.2 4.8* 89.73.0* 82.7 3.0* 76.0 3.0* 93.0 4.1* 30 217.7 14.7* 201.7 17.7* 184.515.0* 174.0 19.3* 197.0 23.6* 60 197.3 16.2* 192.2 21.7* 144.2 12.5*135.8 11.5* 124.8 10.8* 90 182.3 17.7* 185.3 15.0* 151.2 8.9* 141.310.2* 135.8 6.7* 120 163.0 10.3* 154.8 13.2* 146.2 4.6* 132.5 7.9* 130.26.7* *N = 6

TABLE 2 Compound 1 % Inhibition of Dose (mg/kg) Glucose Excursion 0.36.5 3 47.0 10 60.1 30 52.1

Example 3: In Vivo Effects of3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Compound 1) on Glucose Homeostasis (Oral Glucose Tolerance Test (oGTT))in Male 129SVE Mice

Male 129SVE mice (approximately 8-week old) were fasted for 18 h andrandomly grouped (n=6) to receive a GPR119 agonist, (Compound 1), at0.3, 3, or 30 mg/kg (mg/kg body weight). The compound was deliveredorally via a gavage needle (p.o., volume 4 mL/kg) 30 min prior toglucose bolus (3 g/kg) (time=−30 min in FIG. 3), with a separate groupreceiving vehicle (20% hydroxypropyl-beta-cyclodextrin) as control. Attime 0 min. the glucose bolus was administered. Levels of blood glucosewere assessed using a glucometer (One-Touch Ultra™, LifeScan) at time−30 minute (prior to compound administration), at 0 min (at time whenglucose bolus was given), and at 20, 40, 60, 120 min post glucose bolus.The plasma glucose concentration (mg/dL) at the different time points isshown in FIG. 3 and Table 3. Glucose excursion (AUC (area under thecurve) reduction) in compound treated animals relative to vehiclecontrol is given in FIG. 4, and in Table 4. These results demonstratedthat the GPR119 agonist,3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Compound 1), lowered blood glucose after a challenge with glucose in129SVE mice.

TABLE 3 Plasma Glucose (mg/dL) Compound 1 Dose (mg/kg) Time 20% HPCD 0.33.0 30.0 (min) Mean SEM Mean SEM Mean SEM Mean SEM −30 52.2 3.0* 58.54.0* 63.5 3.3* 64.5 7.6* 0 64.7 2.7* 74.2 5.1* 75.2 2.1* 78.7 7.6* 20249.5 9.4* 221.3 13.4* 206.7 11.0* 185.8 8.1* 40 294.3 18.5* 274.8 6.4*233.0 9.8* 216.0 7.7* 60 291.3 13.8* 258.2 9.6* 213.5 12.1* 191.7 10.8*120 185.8 13.3* 154.5 8.5* 138.2 4.6* 138.7 13.4* *N = 6

TABLE 4 Compound 1 % Inhibition of Dose (mg/kg) Glucose Excursion 0.316.9 3 34.8 30 42.1

Example 4: In Vivo Effects of3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Compound 1) on Incretin Hormone GIP Release

Male 129SVE mice (approximately 8-week old) were fasted for 18 h andrandomly grouped (n=6) to receive a GPR119 agonist, (Compound 1), at anoral dose of 0.1, 0.3, 1, 3, 10, or 30 mpk (mg/kg body weight).Compounds were delivered orally via a gavage needle (p.o., volume 4ml/kg), and after 45 min a blood sample was collected to determineplasma total GIP levels. A separate group received vehicle (PET: 80%PEG400, 10% ethanol, 10% Tween80) as control. Plasma GIP levels weredetermined using a Total GIP ELISA kit from Millipore. The results areshown in FIG. 5 and Table 5.

TABLE 5 Compound 1 Total Plasma GIP in Mice Dose (mg/kg) Total GIP,pg/mL Vehicle 36.01 0.1 60.92 0.3 68.21 1 183.8 3 318.5 10 444.8 30695.0

Example 5: Homogeneous Time-Resolved Fluorescence (HTRF®) Assay forDirect cAMP Measurement

The GPR119 agonist, Compound 1, was evaluated in an HTRF® cAMP detectionassay according to the manufacturer's instructions (Cisbio, cAMP Dynamic2 Assay Kit; #62AM4PEJ) using CHO-K1 cells stably expressing the GPR119receptor. Briefly, CHO-K1 cells were transduced with a lentiviral vectorencoding the nucleotide sequence of GPR119 (NCBI mRNA and proteinreference sequences: NM_178471.2 & NP_848566, (GPR119 has also beenreferred to as Glucose-Dependent Insulinotropic Receptor (GDIR)). TheN-terminus of the GPR119 nucleotide sequence was modified to replace thefirst, methionine-coding codon with a nucleotide sequence coding for astandard, nine amino acid, hemagglutinin tag. Following transduction,cells expressing the GPR119 receptor were isolated and a single clonewas isolated following standard dilution-cloning procedures. On the dayof the assay, cultured CHO-GPR119 cells were harvested, suspended inassay buffer and plated into 384-well assay plates (PerkinElmerProxiplate #6008280) at a density of 2,000 cells per well. A cAMPstandard curve was included on each plate. Test compounds weresolubilized in DMSO, serially diluted in DMSO and then diluted in assaybuffer before adding to the cells. Test compounds were evaluated intriplicate, using 10-point, 5-fold serial dilutions starting at 10 μM.The final DMSO concentration in the assay was 0.5%. Compounds and cellswere incubated for 1 h at room temperature and then detection reagentswere added to each well (cAMP-D2 in cell lysis buffer, followed byeuropium cryptate-labeled anti-cAMP antibody). Plates were thenincubated at room temperature for 1 h prior to reading. Time-resolvedfluorescence measurements were collected on PerkinElmer Envision™ or BMGPherastar™ microplate readers. The compoundN-(2-fluoro-4-(methylsulfonyl)phenyl)-6-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-5-nitropyrimidin-4-aminewas used as a positive control in each runset while assay buffercontaining 0.5% DMSO was used as the negative control. Using the HTRF®assay, the EC₅₀ values for the following GPR119 agonists were observed:

-   3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide    (Compound 1), 23.4 nM (n=32);-   3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide    (Compound 2), 27.0 nM (n=9); and-   3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzamide    (Compound 3), 28.2 nM (n=3).

Example 6: In Vivo and In Vitro Metabolism of3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide(Compound 1) Example 6.1: In Vivo Metabolism of Compound 1

Metabolites of Compound 1 were identified in plasma samples collectedfrom different pharmacokinetic studies in various species.

Four species, mouse, rat, dog and monkey were dosed with Compound 1, andplasma samples were collected at predetermined time points from each ofthe species according to specific study protocols. The samples were thenprocessed and subjected to the LC/MS/MS analysis for the identificationand quantification of the metabolites. Three metabolites, designated M1(Compound 2), M2 (Compound 3), and M3 were identified in plasma samplesfrom various species. The M1 metabolite was identified as amono-N-demethylation of Compound 1, and the M2 metabolite was adi-N-demethylation product of Compound 1. The third metabolite M3 (i.e.,3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzoicacid, see below) was determined as a carboxylic acid of Compound 1.

Metabolites M1 and M2 were found to be pharmacologically active (seeExample 5) whereas the M3 metabolite was shown to have substantiallylittle activity (EC₅₀=100 μM, HTRF® assay). Quantification of thesethree metabolites showed that the order of formation was M3>M1>M2 inplasma samples. M3 was found to be the major circulating metabolite inall species. M2 was not observed in dog plasma samples under theanalytical conditions used.

Example 6.2: In Vitro Metabolism of Compound 1 in Liver Microsomes fromVarious Species

Compound 1 was incubated with mouse, rat, dog, monkey and human livermicrosomal protein (0.25 mg/ml final concentration) in 100 mM potassiumphosphate buffer containing 3 mM MgCl₂ and 1 mM EDTA (pH 7.4) for over aperiod of time in the presence or absence of (3-NADPH. The samples werethen processed and the supernatant was analyzed by LC-MS/MS for theidentification and quantification of the metabolites.

Three metabolites, M1 (mono-N-demethylation), M2 (di-N-demethylation)and M3 (carboxylic acid), were identified in the microsomal incubationof all the species including human. Metabolites, M1, M2, and M3 werealso quantified in liver microsomal incubations from all species. Therates of formation of these metabolites were varied across the species,however, the three metabolites observed in the liver microsomes ofpre-clinical species were all found in human liver microsomes (FIGS. 9,10, and 11). The rate of formation of M1 was highest followed by M2 andM3 under the in vitro experimental conditions used. M2 appeared to be asecondary metabolite of M1. Formation of M2 in dog liver microsomes wasnegligible.

Example 7: Powder X-Ray Diffraction

Powder X-ray Diffraction (PXRD) data were collected on an X'Pert PRO MPDpowder diffractometer (PANalytical, Inc.) with a Cu source set at 45 kVand 40 mA, Cu(Kα) radiation and an X'Celerator detector. Samples wereadded to the sample holder and smoothed flat with a spatula and weighpaper. With the samples spinning, X-ray diffractogram was obtained by a12-min scan over the range 5-40°2θ. Diffraction data were viewed andanalyzed with the X'Pert Data Viewer Software, version 1.0a and X'PertHighScore Software, version 1.0b. The powder X-ray diffractogram for theanhydrous crystalline form of Compound 1 is shown in FIG. 6.

Example 8: Differential Scanning Calorimetry

Differential scanning calorimetry (DSC) studies were conducted using aTA Instruments, Q2000 at heating rate 10° C./min. The instruments werecalibrated for temperature and energy using the melting point andenthalpy of fusion of an indium standard. Thermal events (desolvation,melting, etc.) were evaluated using Universal Analysis 2000 software,version 4.1D, Build 4.1.0.16. The DSC thermogram for the anhydrouscrystalline form of Compound 1 is shown in FIG. 7.

Example 9: Thermal Gravimetric Analysis

Thermogravimetric analyses (TGA) were conducted using a TA InstrumentsTGA Q500 or Q5000 at heating rate 10° C./min. The instrument wascalibrated using a standard weight for the balance, and Alumel andNickel standards for the furnace (Curie point measurements). Thermalevents such as weight-loss are calculated using the Universal Analysis2000 software, version 4.1D, Build 4.1.0.16. The TGA thermogram for theanhydrous crystalline form of Compound 1 is shown in FIG. 7.

Example 10: Dynamic Moisture-Sorption Analysis

A dynamic moisture-sorption (DMS) study was conducted using a dynamicmoisture-sorption analyzer, VTI Corporation, SGA-100. Samples wereprepared for DMS analysis by placing 5 mg to 20 mg of a sample in atared sample holder. The sample was placed on the hang-down wire of theVTI balance. A drying step was run, typically at 40° C. and 0.5-1% RHfor 1 h. The isotherm temperature is 25° C. Defined % RH holds typicallyranged from 10% RH to 90% RH, with intervals of 10 to 20% RH. A % weightchange smaller than 0.010% over 10 min, or up to 2 h, whichever occurredfirst, was required before continuing to the next % RH hold. The watercontent of the sample equilibrated as described above was determined ateach % RH hold. The dynamic moisture-sorption profile for the anhydrouscrystalline form of Compound 1 is shown in FIG. 8.

Those skilled in the art will recognize that various modifications,additions, and substitutions to the illustrative examples set forthherein can be made without departing from the spirit of the inventionand are, therefore, considered within the scope of the invention.

Citation of any reference throughout this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

1.-57. (canceled)
 58. An anhydrous crystalline form of the compound3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide,wherein the anhdrous crystalline form has a powder X-ray diffraction(XRPD) pattern comprising peaks, in terms of 2θ, at 13.6°±0.2°,20.1±0.2°, and 25.0°±0.2°.
 59. The anhydrous crystalline form of claim58, wherein the anhdrous crystalline form has a XRPD pattern comprisingpeaks, in terms of 2θ, at 8.6°±0.2°, 13.6°±0.2°, 20.1°±0.2°, 25.0°±0.2°,and 27.2°±0.2°.
 60. The anhydrous crystalline form of claim 58, whereinthe anhdrous crystalline form has a XRPD pattern comprising peaks, interms of 2θ, at 8.6°±0.2°, 13.6°±0.2°, 18.3°±0.2°, 20.1°±0.2°,21.1°±0.2°, 25.0°±0.2°, and 27.2°±0.2°.
 61. The anhydrous crystallineform of claim 58, having a XRPD pattern substantially as shown in FIG.6.
 62. The anhydrous crystalline form of claim 58, having a differentialscanning calorimetry (DSC) thermogram comprising an endothermic peakwith an extrapolated onset temperature between about 143.9° C. and about153.9° C.
 63. The anhydrous crystalline form of claim 58, having a DSCthermogram comprising an endothermic peak with an extrapolated onsettemperature at about 148.9° C.
 64. The anhydrous crystalline form ofclaim 58, having a DSC thermogram substantially as shown in FIG.
 7. 65.The anhydrous crystalline form of claim 58, having a thermogravimetricanalysis (TGA) profile substantially as shown in FIG.
 7. 66. Theanhydrous crystalline form of claim 58, having a dynamic moisturesorption (DMS) analysis profile substantially as shown in FIG.
 8. 67. Acomposition comprising the anhydrous crystalline form of claim 58 and apharmaceutically acceptable carrier.
 68. A method for increasing thesecretion of an incretin or increasing a blood incretin level in anindividual in need thereof, comprising administering to the individual atherapeutically effective amount of the anhydrous crystalline form ofclaim
 58. 69. The method according to claim 68, wherein the incretin isGLP-1.
 70. The method according to claim 68, wherein the incretin isGIP.
 71. The method according to claim 68, wherein the incretin is PYY.72. A method for the treatment of a disorder selected from aGPR119-receptor-related disorder; a condition ameliorated by increasingsecretion of an incretin; a condition ameliorated by increasing a bloodincretin level; a condition characterized by low bone mass; aneurological disorder; a metabolic-related disorder; and obesity; in anindividual in need thereof, comprising administering to the individual atherapeutically effective amount of the anhydrous crystalline form ofclaim
 58. 73. A method for increasing the secretion of an incretin orincreasing a blood incretin level in an individual in need thereof,comprising administering to the individual the anhydrous crystallineform of claim 58 in combination with a second pharmaceutical agent. 74.The method of claim 73, wherein the second pharmaceutical agent isselected from: a DPP-IV inhibitor, a biguanide, an alpha-glucosidaseinhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, ameglitinide, a thiazolidinedione, and an anti-diabetic peptide analogue.75. A method for the treatment of a disorder selected from aGPR119-receptor-related disorder; a condition ameliorated by increasingsecretion of an incretin; a condition ameliorated by increasing a bloodincretin level; a condition characterized by low bone mass; aneurological disorder; a metabolic-related disorder; and obesity; in anindividual in need thereof, comprising administering to the individualthe anhydrous crystalline form of claim 58 in combination with a secondpharmaceutical agent.
 76. The method of claim 75, wherein the secondpharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide,an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, anSGLT2 inhibitor, a meglitinide, a thiazolidinedione, and ananti-diabetic peptide analogue.
 77. A method of treating a conditioncharacterized by low bone mass selected from: osteopenia, osteoporosis,rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar boneloss, osteotomy bone loss, childhood idiopathic bone loss, Paget'sdisease, bone loss due to metastatic cancer, osteolytic lesions,curvature of the spine, and loss of height, wherein the method comprisesadministering to an individual in need thereof an effective amount ofthe anhydrous crystalline form of claim
 58. 78. A method of treating aneurological disorder selected from stroke and Parkinson's disease,wherein the method comprises administering to an individual in needthereof an effective amount of the anhydrous crystalline form of claim58.
 79. A method of treating a metabolic-related disorder selected from:diabetes, type 1 diabetes, type 2 diabetes, inadequate glucosetolerance, impaired glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X,hypertension, pancreatic beta-cell insufficiency, enteroendocrine cellinsufficiency, glycosuria, metabolic acidosis, a cataract, diabeticnephropathy, diabetic neuropathy, peripheral neuropathy, diabeticcoronary artery disease, diabetic cerebrovascular disease, diabeticperipheral vascular disease, diabetic retinopathy, metabolic syndrome, acondition related to diabetes, myocardial infarction, learningimpairment, memory impairment, a neurodegenerative disorder, a conditionameliorated by increasing a blood GLP-1 level in an individual with aneurodegenerative disorder, excitotoxic brain damage caused by severeepileptic seizures, Alzheimer's disease, Parkinson's disease,Huntington's disease, prion-associated disease, stroke, motor-neurondisease, traumatic brain injury, spinal cord injury, and obesity,wherein the method comprises administering to an individual in needthereof an effective amount of the anhydrous crystalline form of claim58.
 80. A method of treating type 2 diabetes, wherein the methodcomprises administering to an individual in need thereof an effectiveamount of the anhydrous crystalline form of claim 58.